AU5651701A - 3-phenyl-imidazo-pyrimidine derivatives as ligands for gaba receptors - Google Patents
3-phenyl-imidazo-pyrimidine derivatives as ligands for gaba receptors Download PDFInfo
- Publication number
- AU5651701A AU5651701A AU56517/01A AU5651701A AU5651701A AU 5651701 A AU5651701 A AU 5651701A AU 56517/01 A AU56517/01 A AU 56517/01A AU 5651701 A AU5651701 A AU 5651701A AU 5651701 A AU5651701 A AU 5651701A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- carbonitrile
- formula
- biphenyl
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003446 ligand Substances 0.000 title description 8
- KTXANHBGXLKMJT-UHFFFAOYSA-N 9-phenylpurine Chemical class C1=NC2=CN=CN=C2N1C1=CC=CC=C1 KTXANHBGXLKMJT-UHFFFAOYSA-N 0.000 title description 2
- 102000005915 GABA Receptors Human genes 0.000 title description 2
- 108010005551 GABA Receptors Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 180
- -1 methyloxadiazolyl Chemical group 0.000 claims description 154
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 239000000651 prodrug Substances 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 229910052723 transition metal Inorganic materials 0.000 claims description 17
- 150000003624 transition metals Chemical class 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 10
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- MZAGXDHQGXUDDX-JSRXJHBZSA-N (e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/C(N)=O MZAGXDHQGXUDDX-JSRXJHBZSA-N 0.000 claims description 9
- 150000002430 hydrocarbons Chemical class 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 9
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- OBARBSRKAUYZAW-UHFFFAOYSA-N 2-[3-[7-(hydroxymethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(CO)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N OBARBSRKAUYZAW-UHFFFAOYSA-N 0.000 claims description 5
- IPHQDEPKMAQVGA-UHFFFAOYSA-N 2-[3-(7-formylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C=O)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N IPHQDEPKMAQVGA-UHFFFAOYSA-N 0.000 claims description 4
- KQZUXBLKOQVLIS-UHFFFAOYSA-N 7-methyl-3-(3-pyridin-2-ylphenyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=N1 KQZUXBLKOQVLIS-UHFFFAOYSA-N 0.000 claims description 4
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- POPNCRWJSXBWPD-UHFFFAOYSA-N 2-(3-imidazo[1,2-a]pyrimidin-3-ylphenyl)benzonitrile Chemical compound N#CC1=CC=CC=C1C1=CC=CC(C=2N3C=CC=NC3=NC=2)=C1 POPNCRWJSXBWPD-UHFFFAOYSA-N 0.000 claims description 3
- MCYJWZGFRUPOHM-UHFFFAOYSA-N 2-[3-(7-acetylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(=O)C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N MCYJWZGFRUPOHM-UHFFFAOYSA-N 0.000 claims description 3
- RCUUCZZNKWYFRX-UHFFFAOYSA-N 2-[3-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound N#CC1=CC=CC=C1C1=CC=CC(C=2N3C=CC(=NC3=NC=2)C2CCC2)=C1 RCUUCZZNKWYFRX-UHFFFAOYSA-N 0.000 claims description 3
- DWTIBQBYGWSGGA-UHFFFAOYSA-N 2-[3-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(OC)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N DWTIBQBYGWSGGA-UHFFFAOYSA-N 0.000 claims description 3
- PEBWTLIJBCZFOA-UHFFFAOYSA-N 2-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N PEBWTLIJBCZFOA-UHFFFAOYSA-N 0.000 claims description 3
- CPZUWMQJYONDPI-UHFFFAOYSA-N 2-[3-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(C)(C)C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N CPZUWMQJYONDPI-UHFFFAOYSA-N 0.000 claims description 3
- VYBPWFTWAKMZPZ-UHFFFAOYSA-N 2-[3-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N VYBPWFTWAKMZPZ-UHFFFAOYSA-N 0.000 claims description 3
- DYDPGRDCZFVBDH-UHFFFAOYSA-N 3-(3-imidazol-1-ylphenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1N1C=CN=C1 DYDPGRDCZFVBDH-UHFFFAOYSA-N 0.000 claims description 3
- YBFCMWXEMSKFLH-UHFFFAOYSA-N 3-[3-(1,2,4-triazol-1-yl)phenyl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1N1C=NC=N1 YBFCMWXEMSKFLH-UHFFFAOYSA-N 0.000 claims description 3
- CBASGEGMEGNJJM-UHFFFAOYSA-N 3-[3-[2-(1,2,4-triazol-1-yl)phenyl]phenyl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1N1C=NC=N1 CBASGEGMEGNJJM-UHFFFAOYSA-N 0.000 claims description 3
- PHFULHKCHWUNSF-UHFFFAOYSA-N 5-fluoro-2-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=C(F)C=C1C#N PHFULHKCHWUNSF-UHFFFAOYSA-N 0.000 claims description 3
- NQMMOMYJRJUOIL-UHFFFAOYSA-N 5-fluoro-2-[3-[7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(C)(O)C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=C(F)C=C1C#N NQMMOMYJRJUOIL-UHFFFAOYSA-N 0.000 claims description 3
- ILOGIPYSSXXLEG-UHFFFAOYSA-N 5-fluoro-2-[3-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound N#CC1=CC(F)=CC=C1C1=CC=CC(C=2N3C=CC(=NC3=NC=2)C(F)(F)F)=C1 ILOGIPYSSXXLEG-UHFFFAOYSA-N 0.000 claims description 3
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000005620 boronic acid group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 238000010561 standard procedure Methods 0.000 claims description 3
- WTUUSUPAECLTPE-UHFFFAOYSA-N 2-[3-(7-cyclopropylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound N#CC1=CC=CC=C1C1=CC=CC(C=2N3C=CC(=NC3=NC=2)C2CC2)=C1 WTUUSUPAECLTPE-UHFFFAOYSA-N 0.000 claims description 2
- PIIIBYJJRSGRIR-UHFFFAOYSA-N 2-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]-1,3-thiazole Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=NC=CS1 PIIIBYJJRSGRIR-UHFFFAOYSA-N 0.000 claims description 2
- AXNHJZODIIXJRU-UHFFFAOYSA-N 2-[3-(7-propan-2-ylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(C)C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N AXNHJZODIIXJRU-UHFFFAOYSA-N 0.000 claims description 2
- UVLUSNVESKDLEM-UHFFFAOYSA-N 2-[3-[7-(difluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(F)F)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N UVLUSNVESKDLEM-UHFFFAOYSA-N 0.000 claims description 2
- SVIKJLMXGIXHSO-UHFFFAOYSA-N 2-[3-[7-(dimethoxymethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(OC)OC)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N SVIKJLMXGIXHSO-UHFFFAOYSA-N 0.000 claims description 2
- ZGYPSRZEYWNCJY-UHFFFAOYSA-N 2-[3-[7-(fluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(CF)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N ZGYPSRZEYWNCJY-UHFFFAOYSA-N 0.000 claims description 2
- CJUIOIXUCSDGOW-UHFFFAOYSA-N 2-[3-[7-(hydroxyiminomethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C=NO)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N CJUIOIXUCSDGOW-UHFFFAOYSA-N 0.000 claims description 2
- NYYGUFWOAMCCRD-UHFFFAOYSA-N 3-(3-pyridin-3-ylphenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CN=C1 NYYGUFWOAMCCRD-UHFFFAOYSA-N 0.000 claims description 2
- GHRRIFKVROHYPE-UHFFFAOYSA-N 3-[3-(1,2,4-triazol-4-yl)phenyl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C(F)(F)F)C=CN2C=1C(C=1)=CC=CC=1N1C=NN=C1 GHRRIFKVROHYPE-UHFFFAOYSA-N 0.000 claims description 2
- YUBHJCGAKPMBHT-UHFFFAOYSA-N 3-[3-(2-cyanophenyl)phenyl]imidazo[1,2-a]pyrimidine-7-carbonitrile Chemical compound C=1N=C2N=C(C#N)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N YUBHJCGAKPMBHT-UHFFFAOYSA-N 0.000 claims description 2
- CIOMKAFWBIKGBL-UHFFFAOYSA-N 3-[3-(2-fluorophenyl)phenyl]-7-methylimidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1F CIOMKAFWBIKGBL-UHFFFAOYSA-N 0.000 claims description 2
- NVPVTBAGESYYAT-UHFFFAOYSA-N 3-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CN=C1C#N NVPVTBAGESYYAT-UHFFFAOYSA-N 0.000 claims description 2
- UENLSNIUXXUNFP-UHFFFAOYSA-N 4-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]-1,3-thiazole Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CSC=N1 UENLSNIUXXUNFP-UHFFFAOYSA-N 0.000 claims description 2
- WVHBHADXFXMCQD-UHFFFAOYSA-N 5-methyl-3-[3-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]phenyl]-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=C(C=CC=2)C=2C=C(C=CC=2)C=2N3C=CC(C)=NC3=NC=2)=N1 WVHBHADXFXMCQD-UHFFFAOYSA-N 0.000 claims description 2
- BMFCPJLUVAWREF-UHFFFAOYSA-N 7-methyl-3-[3-[2-(trifluoromethyl)phenyl]phenyl]imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C(F)(F)F BMFCPJLUVAWREF-UHFFFAOYSA-N 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims description 2
- JFCGDYJEIXWJEY-UHFFFAOYSA-N methyl 3-[3-(2-cyanophenyl)phenyl]imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C=1N=C2N=C(C(=O)OC)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C#N JFCGDYJEIXWJEY-UHFFFAOYSA-N 0.000 claims description 2
- OIQQXLOTYFXVHA-UHFFFAOYSA-N n-[[2-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]phenyl]methylidene]hydroxylamine Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CC=C1C=NO OIQQXLOTYFXVHA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 230000002411 adverse Effects 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 230000000926 neurological effect Effects 0.000 claims 2
- OKRLFGNFWSAYGP-UHFFFAOYSA-N 3-[3-(2-methoxyphenyl)phenyl]-7-methylimidazo[1,2-a]pyrimidine Chemical compound COC1=CC=CC=C1C1=CC=CC(C=2N3C=CC(C)=NC3=NC=2)=C1 OKRLFGNFWSAYGP-UHFFFAOYSA-N 0.000 claims 1
- RZQZDYHJMCEIJV-UHFFFAOYSA-N 7-methyl-3-(3-pyridin-3-ylphenyl)imidazo[1,2-a]pyrimidine Chemical compound C=1N=C2N=C(C)C=CN2C=1C(C=1)=CC=CC=1C1=CC=CN=C1 RZQZDYHJMCEIJV-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 144
- 239000007787 solid Substances 0.000 description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 34
- 108091008681 GABAA receptors Proteins 0.000 description 34
- 102000027484 GABAA receptors Human genes 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 26
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- 235000019439 ethyl acetate Nutrition 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 11
- IIPUMDWNVSSYJT-UHFFFAOYSA-N 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzonitrile Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(C=2C(=CC=CC=2)C#N)=C1 IIPUMDWNVSSYJT-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
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- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- RPHHXEGAGRGVOS-UHFFFAOYSA-N tributyl-[2-(1,2,4-triazol-1-yl)phenyl]stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1N1N=CN=C1 RPHHXEGAGRGVOS-UHFFFAOYSA-N 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
WO 01/90108 PCT/GBO1/02158 3-PHENYL-IMIDAZO-PYRIMIDINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS The present invention relates to a class of substituted imidazo 5 pyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with imidazo[1,2-a]pyrimidine analogues which are substituted in the 3-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states. 10 Receptors for the major inhibitory neurotransmitter, gamma aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA 15 receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six a subunits, four p subunits, three y subunits, one 6 subunit, one s subunit and two p subunits. Although knowledge of the diversity of the GABAA receptor gene 20 family represents a huge step forward in our understanding of this ligand gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an a subunit, a P subunit and a y subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs 25 into cells. As indicated above, 6, s and p subunits also exist, but are present only to a minor extent in GABAA receptor populations. Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at 30 least one a, one P and one y subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit WO 01/90108 PCT/GBO1/02158 -2 combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits). 5 Receptor subtype assemblies which do exist include, amongst many others, alp2y2, a 2 p yl, a2p2/3y2, a3py2/3, a4p6, a5p3y2/3, a6py2 and a6p6. Subtype assemblies containing an al subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing a2 and a3 subunits respectively 10 are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an a5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat. A characteristic property of all known GABAA receptors is the 15 presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine 20 binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the al subunit in combination with a P subunit and y 2 . This is the most abundant GABAA receptor subtype, and is believed to represent almost 25 half of all GABAA receptors in the brain. Two other major populations are the a2py2 and a3py2/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand 30 binding, although the BZ2 subtype may also include certain a5-containing subtype assemblies. The physiological role of these subtypes has hitherto WO 01/90108 PCT/GBO1/02158 been unclear because no sufficiently selective agonists or antagonists were known. It is now believed that agents acting as BZ agonists at alpy2, a2py2 or a3py2 subtypes will possess desirable anxiolytic properties. Compounds 5 which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as "GABAA receptor agonists". The al-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which 10 act at the BZ1 binding site is mediated through GABAA receptors containing the al subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the a2 and/or a3 subunit than with al will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse 15 agonists of the a5 subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease. Also, agents which are antagonists or inverse agonists at al might be employed to reverse sedation or hypnosis caused by al agonists. 20 The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and 25 other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and 30 bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral WO 01/90108 PCT/GBO1/02158 -4 ischemia; attention deficit hyperactivity disorder; speech disorders, including stuttering; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work. Further disorders for which selective ligands for GABAA receptors 5 may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. 10 in paraplegic patients; and hearing disorders, including tinnitus and age related hearing impairment. Selective ligands for GABAA receptors may be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease; and may also be effective as pre-medication prior to anaesthesia or minor procedures such 15 as endoscopy, including gastric endoscopy. In addition, the compounds in accordance with the present invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor. The present invention provides a class of imidazo-pyrimidine 20 derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the a2 and/or 3 and/or c5 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the a2 and/or 3 subunit than with the 25 al subunit; and/or may interact more favourably with the a5 subunit than with the al subunit. The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the a2 and/or 3 and/or a5 subunit, as measured in the assay described hereinbelow, of 200 nM or 30 less, typically of 100 nM or less, and ideally of 20 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, WO 01/90108 PCT/GBO1/02158 -5 suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the a2 and/or a3 and/or a5 subunit relative to the al subunit. However, compounds which are not selective in terms of their binding affinity for the a2 and/or a3 and/or a5 subunit relative to the al subunit 5 are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the al subunit and (i) a full or partial agonist profile at the a2 and/or a3 subunit, and/or (ii) an inverse agonist profile at the a5 subunit. 10 The present invention provides a compound of formula I, or a salt or prodrug thereof: N N Y-Z (I) 15 wherein Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO 2 Ra, -SO 2 NRaRb, 20 -NRaRb, -NRaCORb, -NRaCO 2 Rb, -CORa, -CO 2 Ra, -CONRaRb or -CRa=NORb; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group. The aryl or heteroaryl group Z in the compounds of formula I above 25 may be unsubstituted, or substituted by one or more substituents.
WO 01/90108 PCT/GB01/02158 -6 Typically, the group Z will be unsubstituted, or substituted by one or two substituents. Suitably, the group Z is unsubstituted or monosubstituted. Illustrative substituents on the group Z include halogen, cyano, trifluoromethyl, nitro, C 1
.
6 alkoxy, amino, formyl, C 2
.
6 alkoxycarbonyl, 5 methyloxadiazolyl, triazolyl and -CRa=NORb, wherein Ra and Rb are as defined above. Typical substituents on the group Z include halogen, cyano, nitro, amino, formyl, C 2
.
6 alkoxycarbonyl and -CRa=NORb. For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in 10 the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable 15 acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include 20 alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up 25 to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C 1 ., alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 3 -7 cycloalkyl, C 3
-
7 cycloalkyl(C1.6)alkyl, indanyl, aryl and aryl(C1.)alkyl. The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom 30 preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 WO 01/90108 PCT/GBO1/02158 -7 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3- 7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci-G)alkyl, heteroaryl and heteroaryl(C1.-)alkyl groups. Suitable alkyl groups include straight-chained and branched alkyl 5 groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "C 1
-
6 alkoxy", "C 1
.
6 alkylamino" and "C 1
.
6 alkylsulphonyl" are to be 10 construed accordingly. Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl and dimethylallyl groups. Suitable alkynyl groups include straight-chained and branched 15 alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups. Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl. Typical examples of C 3
-
7 cycloalkyl(C 1 .6)alkyl groups include 20 cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl. Particular indanyl groups include indan-1-yl and indan-2-yl. Particular aryl groups include phenyl and naphthyl, preferably phenyl. Particular aryl(C1.6)alkyl groups include benzyl, phenylethyl, 25 phenylpropyl and naphthylmethyl. Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups. A typical C 3
.
7 heterocycloalkyl(C 1
.
6 )alkyl group is morpholinylmethyl. 30 Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, WO 01/90108 PCT/GBO1/02158 dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups. The expression "heteroaryl(C1.6)alkyl" as used herein includes 5 furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, 10 pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl. The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from C1.6 alkyl, adamantyl, phenyl, halogen, C 1
-
6 haloalkyl, C 1
.
6 aminoalkyl, trifluoromethyl, hydroxy,
C
1
.
6 alkoxy, aryloxy, keto, C 1
.
3 alkylenedioxy, nitro, cyano, carboxy, C 2 -6 15 alkoxycarbonyl, C 2
-
6 alkoxycarbonyl(C1e)alkyl, C2.e alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C 2
.
6 alkylcarbonyl, arylcarbonyl, C1-6 alkylthio, C1.
6 alkylsulphinyl, C 1
.
6 alkylsulphonyl, arylsulphonyl, -NRvRv, -NRvCORw, -NRvCO 2 Rw, -NRvSO 2 Rw, -CH 2 NRvSO 2 Rw, -NHCONRvRw, -CONRRw, -SO 2 NRvRw and -CH 2
SO
2 NRvRw, in which RV and Rw 20 independently represent hydrogen, 01.6 alkyl, aryl or aryl(C1.6)alkyl. The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluoro or chloro. The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be 25 functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. 30 Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the WO 01/90108 PCT/GBO1/02158 -9 compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. 5 In a preferred embodiment, Y represents a chemical bond. In another embodiment, Y represents an oxygen atom. In a further embodiment, Y represents a -NH- linkage. Representative values for the substituent Z include phenyl, pyridinyl, thienyl, thiazolyl, imidazolyl and triazolyl, any of which groups 10 may be optionally substituted. Typical values of Z include phenyl, pyridinyl, thienyl and thiazolyl, any of which groups may be optionally substituted. In a favoured embodiment, Z represents an optionally substituted phenyl group, in particular monosubstituted phenyl. In another embodiment, Z represents optionally substituted pyridinyl, 15 especially pyridin-2-yl or pyridin-3-yl. Examples of suitable substituents on the group Z include fluoro, chloro, cyano, trifluoromethyl, nitro, methoxy, amino, formyl, methoxycarbonyl, methyloxadiazolyl, triazolyl and -CH=NOH. Examples of typical substituents on the group Z include chloro, cyano, nitro, amino, 20 formyl, methoxycarbonyl and -CH=NOH. Examples of particular substituents on the group Z include fluoro, cyano, trifluoromethyl, methoxy, methyloxadiazolyl, triazolyl and -CH=NOH; especially fluoro or cyano; and more especially cyano. Illustrative values of Z include fluorophenyl, cyanophenyl, 25 (cyano)(fluoro)phenyl, trifluoromethyl-phenyl, nitrophenyl, methoxyphenyl, methyloxadiazolyl-phenyl, triazolyl-phenyl, phenyl-CH=NOH, pyridinyl, (amino) (chloro)pyridinyl, cyano-pyridinyl, cyano-thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl-CH=NOH, thiazolyl, imidazolyl and triazolyl. Specific values of Z include 30 cyanophenyl, nitrophenyl, pyridinyl, (amino) (chloro)pyridinyl, cyano thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl-CH=NOH and WO 01/90108 PCT/GBO1/02158 - 10 thiazolyl. Individual values of Z include fluorophenyl, cyanophenyl, (cyano)(fluoro)phenyl, trifluoromethyl-phenyl, methoxyphenyl, methyloxadiazolyl-phenyl, triazolyl-phenyl, phenyl-CH=NOH, pyridinyl, cyano-pyridinyl, thiazolyl, imidazolyl and triazolyl. 5 A particular value of Z is cyanophenyl, especially 2-cyanophenyl. Typically, R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, -ORa, -CORa, -CO 2 Ra or -CRa=NORb. Suitably, R1 represents hydrocarbon, a heterocyclic group, halogen, trifluoromethyl, -ORa, -CORa, -CO 2 Ra or -CRa=NORb. 10 Typical values of Ra include hydrogen and C1.6 alkyl. Suitably, Ra represents hydrogen or methyl. Typical values of Rb include hydrogen, C1.6 alkyl, hydroxy(C 1 .6)alkyl and di(C1.6)alkylamino(C1.6)alkyl. Suitably, Rb represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of 15 Rb include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl. Representative values of R 1 include hydrogen, C1.6 alkyl, halo(C1.)alkyl, dihalo(C 1
.
6 )alkyl, hydroxy(C1.6)alkyl, CJ6 alkoxy(C 1
.
6 )alkyl, di(C1.)alkoxy(C1-6)alkyl, 03.7 cycloalkyl, C 3
.
7 heterocycloalkyl(C1.
6 )alkyl, 20 heteroaryl, C1-6 alkyl-heteroaryl, heteroaryl(C1.6)alkyl, halogen, cyano, trifluoromethyl, C1.6 alkoxy, formyl, C2.6 alkylcarbonyl, C2.6 alkoxycarbonyl and -CRa=NORb, in which Ra and Rb are as defined above. Typical values of R1 include hydrogen, C1-6 alkyl, halo(C1.6)alkyl, dihalo(C1.6)alkyl, hydroxy(C1.6)alkyl, di(C1.6)alkoxy(C.6)alkyl, C3-7 cycloalkyl, C3-7 25 heterocycloalkyl(C1.6)alkyl, heteroaryl(C1-6)alkyl, cyano, trifluoromethyl, C1.6 alkoxy, formyl, C2-6 alkylcarbonyl, C2.6 alkoxycarbonyl and -CRa=NORb, in which Ra and Rb are as defined above. Illustrative values of R1 include C1.6 alkyl, hydroxy(C1.6)alkyl, heteroaryl, halogen, trifluoromethyl, C1.6 alkoxy, formyl, C2.6 alkylcarbonyl, C2-6 alkoxycarbonyl 30 and -CRa=NORb, in which Ra and Rb are as defined above.
WO 01/90108 PCT/GBO1/02158 - 11 Itemised values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl 5 (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, methoxy, formyl, acetyl, 10 methoxycarbonyl and -CR2=NOR3, in which R 2 represents hydrogen or methyl, and R 3 represents hydrogen, hydroxyethyl or dimethylaminoethyl. Selected values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2 15 hydroxyprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR2=NOR3, in which R 2 and R 3 are as defined above. Individual values of R1 include hydrogen, methyl, fluoromethyl, 20 difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR2=NOR3, in which R 2 and R 3 are as defined above. 25 Specific values of R1 include methyl, hydroxymethyl, hydroxyethyl, furyl, chloro, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR 2 =NOR3, in which R 2 and R 3 are as defined above. A particular value of R1 is C1.6 alkyl, especially methyl. In one favoured embodiment, R 1 represents 2-hydroxyprop-2-yl. In 30 another favoured embodiment, R1 represents trifluoromethyl. Suitably, R 2 is hydrogen.
WO 01/90108 PCT/GBO1/02158 - 12 Suitably, R3 represents hydrogen or dimethylaminoethyl, especially hydrogen. A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs 5 thereof: R N N (IIA) wherein 10 Z is as defined above;
R
1 1 represents hydrogen, C 1
.
6 alkyl, halo(C1.6)alkyl, dihalo(C 1
.
6 )alkyl, hydroxy(C1.)alkyl, C 1
.
6 alkoxy(C 1
.
6 )alkyl, di(C1-6)alkoxy(C1.6)alkyl, C 3 -7 cycloalkyl, C 3
-
7 heterocycloalkyl(C1.6)alkyl, heteroaryl, C 1
.
6 alkyl heteroaryl, heteroaryl(C1.6)alkyl, halogen, cyano, trifluoromethyl, C1.6 15 alkoxy, formyl, C 2
.
6 alkylcarbonyl, C 2 .6 alkoxycarbonyl or -CR4=NOR5;
R
4 represents hydrogen or C 1
.
6 alkyl; and R5 represents hydrogen, C 1
.
6 alkyl, hydroxy(C1.6)alkyl or di(C1.6)alkylamino(C1.e)alkyl. The present invention also provides a compound of formula IIA as 20 depicted above, or a salt or prodrug thereof, wherein
R
11 represents C 1
.
6 alkyl, hydroxy(C 1
.
6 )alkyl, heteroaryl, halogen, trifluoromethyl, C 1
.
6 alkoxy, formyl, C2- 6 alkylcarbonyl, C 2
-
6 alkoxycarbonyl or -CR 4
=NOR
5 ; and Z, R 4 and R 5 are as defined above. 25 Suitably, R 4 represents hydrogen or methyl, especially hydrogen.
WO 01/90108 PCT/GBO1/02158 - 13 Suitably, R5 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R 5 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R 5 represents hydrogen or dimethylaminoethyl, especially hydrogen. 5 Where R 1 1 represents C 3
.
7 heterocycloalkyl(C1.6)alkyl, this group is suitably morpholinylmethyl. Where R1 represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl, especially furyl. Where R1 represents C 1
.
6 alkyl-heteroaryl, this group is suitably 10 methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3 methyl-[1,2,4]oxadiazol-5-yl). Where R" represents heteroaryl(C1.6)alkyl, this group is suitably imidazolylmethyl or triazolylmethyl. Typical values of R11 include hydrogen, C 1
.
6 alkyl, halo(C1..e)alkyl, 15 dihalo(C1.e)alkyl, hydroxy(C1.6)alkyl, di(C1.6)alkoxy(C1.)alkyl, C 3
.
7 cycloalkyl, C 3
-
7 heterocycloalkyl(C1.6)alkyl, heteroaryl(CI.)alkyl, cyano, trifluoromethyl, CI.
6 alkoxy, formyl, C 2
.
6 alkylcarbonyl, C 2
.
6 alkoxycarbonyl and -CR 4
=NOR
5 , in which R 4 and R 5 are as defined above. Itemised values of R 11 include hydrogen, methyl, fluoromethyl, 20 difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), tert-butyl, 25 cyclopropyl, cyclobutyl, morpholinylmethyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR 2
=NOR
3 , in which R 2 and R3 are as defined above. 30 Selected values of R 1 1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl WO 01/90108 PCT/GB01/02158 - 14 (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2 hydroxyprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR 2 =NOR3, in which R 2 and R 3 are as defined 5 above. Individual values of R" include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, 10 methoxy, formyl, acetyl, methoxycarbonyl and -CR 2 =NOR3, in which R 2 and R 3 are as defined above. Representative values of R 1 1 include methyl, hydroxymethyl, hydroxyethyl, furyl, chloro, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and -CR 2 =NOR3, in which R 2 and R 3 are as defined 15 above. A particular value of R" is C 1
.
6 alkyl, especially methyl. In one favoured embodiment, R" represents 2-hydroxyprop-2-yl. In another favoured embodiment, R 11 represents trifluoromethyl. One representative subset of the compounds of formula IIA above is 20 represented by the compounds of formula IIB, and salts and prodrugs thereof: HSC N N z (IIB) 25 wherein Z is as defined above.
WO 01/90108 PCT/GBO1/02158 - 15 Another representative subset of the compounds of formula IIA above is represented by the compounds of formula IIC, and salts and prodrugs thereof: R N N
R
R 7 5 (IIC) wherein X represents CH or N;
R
6 represents fluoro, cyano, trifluoromethyl, methoxy, 10 methyloxadiazolyl, triazolyl or -CR 2 =NOR3;
R
7 represents hydrogen or fluoro; and
R
2 , R and R 11 are as defined above. In a favoured embodiment, X represents CH. In another embodiment, X represents N. 15 In a particular embodiment, R 6 represents cyano. In one embodiment, R 7 is hydrogen. In another embodiment, R7 is fluoro. In a specific embodiment of the compounds of formula IIC, X is CH,
R
6 is cyano, and R7 is hydrogen. 20 A further representative subset of the compounds of formula IIA above is represented by the compounds of formula IID, and salts and prodrugs thereof: WO 01/90108 PCT/GBO1/02158 - 16 R N N NN \ N (IID) wherein W represents CH or N; and 5 R 11 is as defined above. In one embodiment, W represents CH. In another embodiment, W represents N. In relation to formula IID above, the substituent R11 favourably represents trifluoromethyl. 10 Specific compounds within the scope of the present invention include: 3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 15 3'-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 carbonitrile; 3'-(7-acetylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-isopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-cyclopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 20 3'-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-fluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; WO 01/90108 PCT/GBO1/02158 - 17 3'- (7-formylimidazo [1, 2-a]pyrimidin- 3-yl)biphenyl-2-carbonitrile; 3'- (7-hydroxyi'minomethyli*mi'dazo [1, 2-a]pyrimidin- 3-yl)biphenyl-2 carbonitrile; 3- (2' -cyanobiphenyl- 3-yl)imicldazo [1, 2-a]pyrirnidine -7-carbonitrile; 5 3- (2'-methoxybiphenyl-3-yl)- 7-methylimi'dazo [1, 2-a]pyrimidine; 3- (2'-cyanobiphenyl- 3-yl)imidazo [1, 2-alpyrimidine-7-carboxylic acid methyl ester; 3'- (7-dirnethoxymethylimidazo[1, 2-ajpyrimidin- 3-yl)biphenyl-2 carbonitrile; 10 3'- [7- ([1,2, 4]triazol- 1-ylmethyl)imidazo [1, 2-a]pyrirnidin-3-yl]biphenyl-2 carbonitrile; 3'- (7-difluoromethylirnidazo [1, 2-a]pyri'midin- 3-yl)biphenyl-2-carbonitrile; 7-methyl- 3- [3- (pyridin- 3-yl)phenyl]irnidazo [1, 2-a]pyrimidine; 7-methyl-3- [3'- (5-methyl- [1,2,4] oxadi'azol- 3-yl)biphenyl- 3-yl]imidazo [1,2 15 alpyrimidine; 7-methyl- 3- [2'- (3-methyl- [1,2, 4]oxadiazol- 5-yl)biphenyl- 3-ylljimidazo [1,2 a]pyrimidine; 7-methyl- 3- [3- (thiazol-4-yl)phenyl]imidazo [1, 2-alpyrirnidine; 3'- (7-methylimidazo [1, 2-a]pyrimidin- 3-yl)biphenyl-2-carbaldehyde oxirne; 20 3- [3- (7-methylimidazo [1, 2-a]pyrimidin- 3-yl)pheniyl]pyridine-2-carbonitrile; 7-methyl- 3- [3- (pyridin-2-yl)phenyl]imidazo [1, 2-a]pyrimidine; 7-methyl- 3- [3- (thiazol-2-yl)phenyl]imidazo [1, 2-a]pyrimidine; 7-methyl- 3- (2' -trifluoromethylbiphenyl- 3-yl)imidazo [1, 2-a]pyrirniLdine; 3- (2' -fluorobiphenyl- 3-yl)-7 -methylimidazo [1, 2-a]pyrimidine; 25 4-fluoro- 3'- (7-methylimidazo [1, 2-a]pyrimidin- 3-yl)biphenyl-2-carbonitrile; 3- [3- (imidazol- 1-yl)phenyl] -7-trifluoromethylimidazo [1, 2-a]pyrimidine; 3- [3- ([1,2, 4]triazol- 1-yl)phenyl] -7-trifluoromethylimidazo [1, 2-a]pyrimidine; 3- [2' -([1,2, 4]triazol- 1-yl)biphenyl-3-yl] -7 -trifluoromethylimidazo [1,2 a]pyrimidine; 30 3'- [7- (morpholi'n-4-ylmethyl)imidazo [1, 2-a]pyrimidin- 3-yl]biphenyl-2 carbonitrile; WO 01/90108 PCT/GBO1/02158 - 18 4-fluoro-3'-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 carbonitrile; 4-fluoro-3'-[7-(2-hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 carbonitrile; 5 3-[3-(pyridin-3-yl)phenyl]-7-trifluoromethylimicdazo[1,2-a]pyrimidine; 3-[3-([1,2,4]triazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine; and salts and prodrugs thereof. Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to 10 a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from 15 epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof. The binding affinity (Ki) of the compounds according to the present 20 invention for the a3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The a3 subunit binding affinity (Ki) of the anxiolytic compounds of the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less. The anxiolytic compounds according to the present invention will 25 ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC 2 o response in stably transfected recombinant cell lines expressing the 3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at 30 most a 10%, potentiation of the GABA EC 2 o response in stably transfected WO 01/90108 PCT/GBO1/02158 - 19 recombinant cell lines expressing the al subunit of the human GABAA receptor. The potentiation of the GABA EC 2 0 response in stably transfected cell lines expressing the a3 and al subunits of the human GABAA receptor 5 can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk fibroblast cells. 10 The compounds according to the present invention may exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are likely to be substantially non-sedating, as 15 may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213). The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block 20 pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501. In another aspect, the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing 25 conditions such as Alzheimer's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, 30 Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948.
WO 01/90108 PCT/GBO1/02158 - 20 Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson's disease and Down Syndrome. 5 Any of these conditions may be attributable to substance abuse or withdrawal. Examples of dementia include dementia of the Alzheimer's type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson's disease or 10 Creutzfeld-Jakob disease. In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier". Preferably, the compounds of the invention will be capable of exerting their beneficial 15 therapeutic action following administration by the oral route. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, 20 sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with 25 a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a 30 pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active WO 01/90108 PCT/GBO1/02158 - 21 ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described 5 above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For 10 example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A 15 variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection 20 include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as 25 tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. In the treatment of neurological disorders, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be 30 administered on a regimen of 1 to 4 times per day.
WO 01/90108 PCT/GBO1/02158 - 22 The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV: R IN N M L Y-Z 5(111) (IV) wherein Y, Z and R1 are as defined above, Li represents a suitable leaving group, and M 1 represents a boronic acid moiety -B(OH) 2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or 10 neopentyl glycol, or M1 represents -Sn(Alk) 3 in which Alk represents a C 1
.
6 alkyl group, typically n-butyl; in the presence of a transition metal catalyst. The leaving group L' is typically a halogen atom, e.g. bromo. The transition metal catalyst of use in the reaction between 15 compounds III and IV is suitably tetrakis(triphenylphosphine) palladium(0). The reaction is conveniently carried out at an elevated temperature in a solvent such as NN-dimethylacetamide, 1,4-dioxane or tetrahydrofuran, advantageously in the presence of potassium phosphate, copper(I) iodide or sodium carbonate. Alternatively, the transition metal 20 catalyst employed may be dichloro[1,1'-bis(diphenylphosphino) ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as NN-dimethylformamide. In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a 25 compound of formula V with a compound of formula VI: WO 01/90108 PCT/GBO1/02158 - 23 R N N L NL M (VI) wherein Y, Z, R1, L 1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. 5 In another procedure, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII: R N N M-- z Li 10 (VI)(III) wherein Z, R1, Li and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. 15 In the compounds of formula VII above, the leaving group L' is typically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. bromo. Alternatively, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which 20 comprises reacting a compound of formula IX with a compound of formula
X:
WO 01/90108 PCT/GBO1/02158 - 24 R N N
L-
11_ M (IX) ( wherein Z, R 1 , L 1 and M1 are as defined above; in the presence of a 5 transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In an additional procedure, the compounds according to the present invention in which Y represents an oxygen atom may be prepared by a process which comprises reacting a compound of formula X as defined 10 above with a compound of formula XI: R N N OH (XI) wherein R1 is as defined above. 15 The reaction is conveniently carried out under basic conditions, e.g. using sodium hydride in a solvent such as NN-dimethylformamide, typically at an elevated temperature which may be in the region of 120 0 C. In a further procedure, the compounds according to the present invention in which Y represents a -NH- linkage may be prepared by a WO 01/90108 PCT/GBO1/02158 - 25 process which comprises reacting a compound of formula X as defined above with a compound of formula XII: R N NH2 (XII) 5 wherein RI is as defined above. In relation to the reaction between compounds X and XII, the leaving group L' in the compounds of formula X may suitably represent fluoro. 10 The reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120'C, in a solvent such as NN-dimethylformamide. Where M 1 in the intermediates of formula IV and IX above represents a cyclic ester of a boronic acid moiety -B(OH) 2 formed with 15 pinacol or neopentyl glycol, the relevant compound IV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VIA or VIIA: L 2 R N -N NN Y-Z 2 L (VIA) (VIIA) 20 WO 01/90108 PCT/GBO1/02158 - 26 wherein Y, Z and R1 are as defined above, and L 2 represents hydroxy or a suitable leaving group; in the presence of a transition metal catalyst. Where L 2 represents a leaving group, this is typically triflyloxy; or a halogen atom such as bromo. 5 The transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis(neopentyl glycolato)diborane and compound VIA or VIIA is suitably dichloro [1, 1'-bis (diphenylphosphino)ferrocene] palladium(II). The reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with 10 dimethylsulfoxide, typically in the presence of 1,1' bis(diphenylphosphino)ferrocene and/or potassium acetate. Where L 1
/L
2 in the intermediates of formula VII/VIIA above represents triflyloxy, the relevant compound VII/VIIA may be prepared by reacting the appropriate compound of formula XI as defined above with 15 triflic anhydride, typically in the presence of pyridine. Analogous conditions may be utilised for converting an intermediate of formula VIA above wherein L 2 represents hydroxy into the corresponding compound of formula VI/VIA wherein L 1
/L
2 represents triflyloxy. The intermediates of formula XI above may suitably be prepared 20 from the appropriate methoxy-substituted precursor of formula XIII: R N ~N
OCH
3 (XIII) wherein RI is as defined above; by treatment with hydrogen bromide, 25 typically in acetic acid at reflux.
WO 01/90108 PCT/GBO1/02158 - 27 The intermediates of formula XII and XIII above may be prepared by reacting a compound of formula III as defined above with the appropriate compound of formula XIV: M Y1 5 (XIV) wherein M1 is as defined above, and Y 1 represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In 10 particular, the transition metal catalyst of use in the reaction between compounds III and XIV is suitably tetrakis(triphenylphosphine) palladium(0), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate. 15 Where M1 in the intermediates of formula V above represents -Sn(Alk) 3 and Alk is as defined above, this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk) 3 Sn-Hal, in which Hal represents a halogen atom, typically chloro. The reaction is conveniently effected by treating compound III 20 with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk) 3 Sn-Hal. Where L' in the intermediates of formula III above represents bromo, this compound may be prepared by bromination of the 25 corresponding compound of formula XV: WO 01/90108 PCT/GBO1/02158 - 28 R N N -2 wherein R1 is as defined above; typically by treatment with bromine in methanol, in the presence of sodium acetate and optionally also potassium 5 bromide. The intermediates of formula XV may be prepared by reacting chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, e.g. the dimethyl or diethyl acetal thereof, with the requisite compound of formula XVI: 10 N NH (xv1) wherein RI is as defined above. Where chloroacetaldehyde or bromoacetaldehyde is utilised as one 15 of the reactants, the reaction is conveniently carried out by heating the reactants under basic conditions in a suitable solvent, e.g. sodium methoxide or sodium hydrogencarbonate in a lower alkanol such as methanol and/or ethanol at the reflux temperature of the solvent. Where an acetal derivative of chloroacetaldehyde or bromoacetaldehyde, e.g. the 20 dimethyl or diethyl acetal thereof, is utilised as one of the reactants, the reaction is conveniently effected by heating the reactants under acidic conditions in a suitable solvent, e.g. aqueous hydrobromic acid in a lower alkanol such as methanol or ethanol, typically at the reflux temperature of the solvent.
WO 01/90108 PCT/GB01/02158 - 29 In a still further procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula XVI as defined above with a compound of formula XVII: 5
L
3 CHO Y-Z (XVII) wherein Y and Z are as defined above, and L represents a suitable leaving group; under conditions analogous to those described above for the 10 reaction between chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, and compound XVI. The leaving group L3 is suitably a halogen atom, e.g. bromo. The intermediates of formula XV may also be prepared by reacting a compound of formula XVIII or XIX with the compound of formula XX, or 15 with an acid addition salt of the latter compound, e.g. the hemisulfate salt: R 0 0
H
2 N N O-AlkR HN CHO-Alk 0-Alk (XVIII) (XIX) (XX) wherein R1 is as defined above, and Alk1 represents C 1 . alkyl. 20 Typical values of Alki include methyl and ethyl. The reaction is conveniently effected by heating the reactants under basic conditions in a suitable solvent, e.g. a lower alkoxide such as sodium WO 01/90108 PCT/GBO1/02158 - 30 methoxide or ethoxide in a lower alkanol such as methanol or ethanol, typically at the reflux temperature of the solvent. In a yet further procedure, the compounds according to the present invention wherein RI represents an aryl or heteroaryl moiety may be 5 prepared by a process which comprises reacting a compound of formula XXI with a compound of formula XXII: N N Rla -MI Y-Z (XXI) (XXII) 10 wherein Y, Z and M1 are as defined above, Ria represents an aryl or heteroaryl moiety, and L 4 represents a suitable leaving group; in the presence of a transition metal catalyst. The leaving group L 4 is typically a halogen atom, e.g. chloro. The transition metal catalyst of use in the reaction between 15 compounds XXI and XXII is suitably tetrakis(triphenylphosphine) palladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as NN-dimethylacetamide, typically in the presence of potassium phosphate or in the presence of lithium chloride and copper(I) iodide. Alternatively, the transition metal 20 catalyst may suitably be tris(dibenzylideneacetone)palladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri-tert butylphosphine and cesium carbonate. Where L 4 in the compounds of formula XXII above represents a 25 halogen atom, these compounds correspond to compounds of formula I as WO 01/90108 PCT/GBO1/02158 - 31 defined above wherein R1 represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention. The compound of formula XX above is commercially available from 5 the Sigma-Aldrich Company Ltd., Dorset, United Kingdom. Where they are not commercially available, the starting materials of formula VI, VIII, X, XIV, XVI, XVII, XVIII, XIX and XXI may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. 10 It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I wherein R 1 represents -C(O-Alk1) 2 Ra initially obtained, wherein Alki is as 15 defined above, may be converted into the corresponding compound of formula I wherein R 1 represents -CORa by hydrolysis with a mineral acid, typically aqueous hydrochloric acid. A compound wherein R1 represents formyl may be reduced with sodium triacetoxyborohydride to the corresponding compound wherein R1 represents hydroxymethyl. A 20 compound of formula I wherein R 1 represents hydroxymethyl may be oxidised to the corresponding compound of formula I wherein R 1 represents formyl by treatment with manganese dioxide. The formyl derivative thereby obtained may be condensed with a hydroxylamine derivative of formula H 2 N-ORb to provide a compound of formula I wherein 25 Ri represents -CH=NORb. Furthermore, a compound of formula I wherein R' represents -CH=NOH may be treated with triethylamine in the presence of 1,1'-carbonyldiimidazole to afford a corresponding compound of formula I wherein RI represents cyano. Alternatively, the compound of formula I wherein R1 represents formyl may be reacted with a Grignard 30 reagent of formula RaMgBr to afford a compound of formula I wherein R1 represents -CH(OH)Ra, and this compound may in turn be oxidised using WO 01/90108 PCT/GBO1/02158 - 32 manganese dioxide to the corresponding compound of formula I wherein R1 represents -CORa. The latter compound may then be condensed with a hydroxylamine derivative of formula H 2 N-ORb to provide a compound of formula I wherein R 1 represents -CRa=NORb. A compound of formula I 5 wherein Ri represents -CH(OH)Ra may be converted into the corresponding compound of formula I wherein R 1 represents -CHFRa by treatment with (diethylamino)sulfur trifluoride (DAST). Similarly, a compound of formula I wherein R1 represents -CORa may be converted into the corresponding compound of formula I wherein R1 represents -CF 2 Ra by 10 treatment with DAST. A compound of formula I wherein R1 represents amino may be converted into the corresponding compound of formula I wherein RI represents chloro by diazotisation, using sodium nitrite, followed by treatment with copper(I) chloride. A compound of formula I wherein R1 represents -COCH 3 may be treated with thioacetamide in the 15 presence of pyridinium tribromide to furnish the corresponding compound of formula I wherein R1 represents 2-methylthiazol-5-yl. Moreover, a compound of formula I wherein R 1 is formyl may be treated with (p-tolylsulfonyl)methyl isocyanide (TosMIC) in the presence of potassium carbonate to afford the corresponding compound of formula I wherein R1 20 represents oxazol-5-yl. A compound of formula I wherein R 1 represents hydroxymethyl may be treated with carbon tetrabromide and triphenylphosphine to afford the corresponding compound of formula I wherein R 1 represents bromomethyl, which may then be reacted (typically in situ) with the sodium salt of imidazole or 1H-[1,2,4]triazole to provide a 25 compound of formula I wherein RI represents imidazol-1-ylmethyl or [1,2,4]triazol-1-ylmethyl respectively; or with the sodium salt of 1H [1,2,3]triazole to provide a mixture of compounds of formula I wherein R1 represents [1,2,3]triazol-1-ylmethyl and [1,2,3]triazol-2-ylmethyl; or with morpholine to provide a compound of formula I wherein R1 represents 30 morpholin-4-ylmethyl.
WO 01/90108 PCT/GBO1/02158 - 33 Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or 5 column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system. Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques 10 such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of 15 diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of 20 the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic 25 Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The following Examples illustrate the preparation of compounds 30 according to the invention.
WO 01/90108 PCT/GBO1/02158 - 34 The compounds in accordance with this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the a2 and/or a3 and/or a5 subunit stably expressed in Ltk- cells. 5 Reagents " Phosphate buffered saline (PBS). " Assay buffer: 10 mM KH 2
PO
4 , 100 mM KCl, pH 7.4 at room temperature. " [ 3 H]-Flumazenil (18 nM for alp3y2 cells; 18 nM for a2p 3 y 2 cells; 10 nM 10 for a3p3y2 cells; 10 nM for a5p3y2 cells) in assay buffer. * Flunitrazepam 100 ptM in assay buffer. " Cells resuspended in assay buffer (1 tray to 10 ml). Harvesting Cells 15 Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets 20 are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells. Assay Can be carried out in deep 96-well plates or in tubes. Each tube contains: 25 e 300 1Ll of assay buffer. * 50 pl of [ 3 H]-flumazenil (final concentration for alp3y2: 1.8 nM; for a2p3y2: 1.8 nM; for a3p3y2: 1.0 nM; for a5p3y2: 1.0 nM). * 50 1d of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to 30 determine non-specific binding), 10 pLM final concentration. e 100 1i of cells.
WO 01/90108 PCT/GBO1/02158 - 35 Assays are incubated for 1 hour at 400C, then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 5 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be 10 calculated for each test compound. The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [3H]-flumazenil from the a2 and/or a3 and/or a5 subunit of the human GABAA receptor of 100 nM or less. 15 EXAMPLE 1 3'-(7-Methylimidazor,2-alpyrimidin-3-vl)biphenyl-2-carbonitrile A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3 20 aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol),and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in 1,2 dimethoxyethane (50 ml) and 2M sodium carbonate solution (25 ml) was heated at 80*C for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 ml) and water (400 ml). The 25 organics were washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (0-25%) gave 3'-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid (9.5 g, 98%): 6 H (400 30 MHz, CD C1 3 ) 3.79 (2H, br), 6.75 (1H, ddd, J 8, 3 and 1), 6.84 (1H, dd, J 3 and 3), 6.92 (1H, dd, J 8 and 3), 7.25 (1H, dd, J 8 and 8), 7.40 (1H, ddd, J WO 01/90108 PCT/GBO1/02158 - 36 8, 8 and 1), 7.50 (1H, dd, J8 and 1), 7.62 (1H, ddd, J8, 8 and 1), 7.73 (1H, dd, J8 and 1). A solution of 3'-aminobiphenyl-2-carbonitrile (10.9 g, 56 mmol) in 1,4-dioxane (30 ml) was treated with a solution of 25% aqueous sulfuric 5 acid (150 ml). The resulting suspension was cooled to 0*C before being treated dropwise over 10 minutes with a solution of sodium nitrite (4.6 g, 67 mmol) in water (10 ml). After stirring at 0*C for 30 minutes the reaction was poured into hot (70*C) water (500 ml). On cooling to ambient temperature the product was extracted into ethyl acetate (500 ml), the 10 organics were washed with water (300 ml), brine (300 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded 3'-hydroxybiphenyl-2-carbonitrile as a dark oil (7.1 g, 65%): 6 H (400 MHz, CDCls) 5.40 (1H, br), 6.92 (1H, ddd, J 8, 3 and 1), 7.04 (1H, dd, J 3 and 3), 7.11 (1H, ddd, J8, 3 and 1), 7.35 (1H, dd, J8 and 8), 7.44 (1H, ddd, J8, 8 15 and 1), 7.51 (1H, dd, J8 and 1), 7.64 (1H, ddd, J8, 8 and 1), 7.75 (1H, dd, J8 and 1). 3'-Hydroxybiphenyl-2-carbonitrile (0.48 g, 2.47 mmol) and dry pyridine (0.98 g, 12.35 mmol) were dissolved in dichloromethane (7 ml) and cooled to 0 0 C before dropwise addition of trifluoromethanesulfonic 20 anhydride (1.04 g, 3.70 mmol) over 5 min. The mixture was stirred at 0 0 C for 10 min and then at 25 0 C for 1 h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (200 ml) and water (150 ml). The organic layer was washed with brine (150 ml), dried over anhydrous sodium sulfate and evaporated to give a brown oil. Purification 25 by silica gel chromatography eluting with isohexane on a gradient of ethyl acetate (0-30%) gave trifluoromethanesulfonic acid 2'-cyanobiphenyl-3-yl ester as a yellow oil (544 mg, 67%): 8H (400 MHz, CDCl 3 ) 7.37 (1H, ddd, J 8, 3 and 1), 7.39 (1H, dd, J 3 and 3), 7.50-7.60 (2H, m), 7.61-7.65 (2H, m), 7.64 (1H, td, J 8 and 1), 7.80 (1H, dd, J 8 and 1). 30 Trifluoromethanesulfonic acid 2'-cyanobiphenyl-3-yl ester (0.55 g, 1.66 mmol), potassium acetate (0.49 g, 4.98 mmol) and WO 01/90108 PCT/GBO1/02158 - 37 bis(pinacolato)diboron (0.55 g, 2.16 mmol) were dissolved in 1,4-dioxane (10 ml) and the mixture degassed with N2for 15 min. Dichloro[1,1' bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (41 mg, 0.05 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (28 mg, 0.05 5 mmol) were then added and the mixture heated at 85'C for 18 h. The mixture was cooled to ambient temperature, filtered and the filter cake washed with diethyl ester. The filtrate was evaporated to dryness and partitioned between diethyl ether (25 ml) and 1N sodium hydroxide solution (25 ml). The aqueous layer was washed with more diethyl ether 10 then made acidic (pH 6) with 4N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo to give 3'-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as a cream coloured solid (430 mg, 85%): 8 H (400 MHz, CDCl 3 ) 1.36 (12H, s), 7.43 (1H, ddd, J8, 8 and 1.5), 7.48-7.57 (2H, m), 7.62 (2H, ddd, J8, 8 and 1.5), 7.68 15 7.71 (1H, in), 7.74-7.77 (1H, in), 7.87-7.90 (1H, in), 7.92-7.94 (1H, in). Sodium methoxide (1.62 g, 30 mmol) was added to a stirred solution of 2-aminoimidazole hemisulfate (2.64 g, 20 mmol) and 1,1-dimethoxy-3 butanone (2 ml) in ethanol (25 ml). The mixture was heated under reflux for 8 h, allowed to cool to room temperature then pre-adsorbed directly 20 onto silica. Purification by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-4%) gave a 95:5 mixture of 7-methylimidazo[1,2-a]pyrimidine and 5 methylimidazo[1,2-a]pyrimidine respectively (1.68 g, 64%) as a white crystalline solid: 8H (400 MHz, CDCl 3 , 7-methyl isomer) 2.64 (3H, s), 6.74 25 (1H, d, J 7), 7.45 (1H, d, J 1), 7.73 (1H, d, J 1), 8.29 (1H, d, J 7). 7-Methylimidazo[1,2-a]pyrimidine (100 mg, 0.75 mmol) and sodium acetate (74 mg, 0.90 mmol) were dissolved in methanol (2 ml) which had been saturated with potassium bromide and this mixture was cooled to -10*C before dropwise addition of bromine (132 mg, 0.83 mmol) over 5 min. 30 On complete addition the mixture was quenched by addition of IM sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was WO 01/90108 PCT/GBO1/02158 - 38 treated with water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (3 x 40 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give an off white solid. This solid was 5 purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) to give 3-bromo-7 methylimidazo[1,2-a]pyrimidine (100 mg, 63%) as a white crystalline solid: 8H (400 MHz, CDC1 3 ) 2.67 (3H, s), 6.87 (1H, d, J 7), 7.71 (1H, s), 8.27 (1H, d, J 7). 10 3-Bromo-7-methylimidazo[1,2-a]pyrimidine (100 mg, 0.47 mmol), potassium phosphate (200 mg, 0.94 mmol) and 3'-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (215 mg, 0.70 mmol) were dissolved in NN-dimethylacetamide (2 ml) and the mixture degassed with
N
2 for 15 min. Tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.002 15 mmol) was added and the mixture heated at 65*C for 24 h. The mixture was allowed to cool to room temperature, diluted with water (20 ml) and saturated sodium hydrogencarbonate solution (20 ml) then extracted with ethyl acetate (2 x 75 ml). The combined organic fractions were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to 20 give a black oil. The oil was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1 2%). The solid obtained was triturated with diethyl ether to furnish 3'-(7 methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (120 mg, 82%) as a white powder: SH (400 MHz, CDCl 3 ) 2.67 (3H, s), 6.83 (1H, d, J 7), 7.49 25 (1H, td, J8 and 1), 7.55-7.75 (6H, in), 7.82 (1H, dd, J8 and 1), 7.85 (1H, s), 8.82 (1H, d, J7). EXAMPLE 2 30 3'-(Imidazo[1,2-alpyrimidin-3-yl)biphenvl-2-carbonitrile WO 01/90108 PCT/GBO1/02158 - 39 A solution of 2-aminopyrimidine (0.5 g, 5.26 mmol), bromoacetaldehyde diethyl acetal (2.07 g, 10.5 mmol) and 48% aqueous hydrobromic acid (0.5 ml) in ethanol (5 ml) was heated at reflux for 18 h. The reaction was cooled and pre-adsorbed directly onto silica gel. 5 Purification by flash chromatography eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-3%) gave a solid which was triturated with 5% diethyl ether in isohexane to afford imidazo[1,2-a]pyrimidine (0.51 g, 82%) as a tan solid: 8H (400 MHz, CDCl 3 ) 6.92 (1H, dd, J 7 and 4), 7.59 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, dd, J 10 7 and 2), 8.58 (iH, dd, J 7 and 2). Imidazo[1,2-a]pyrimidine (0.20 g, 1.68 mmol) was brominated as described in Example 1 to give 3-bromoimidazo[1,2-a]pyrimidine (0.29 g, 87%) as a white solid: 6 H (400 MHz, CDCl 3 ) 7.02 (1H, dd, J 7 and 4), 7.83 (1H, s), 8.43 (1H, dd, J 7 and 2), 8.59 (1H, dd, J 7 and 2). 15 3-Bromoimidazo[1,2-a]pyrimidine (0.29 g, 1.68 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2 carbonitrile as described in Example 1 to give 3'-(imidazo[1,2-a]pyrimidin 3-yl)biphenyl-2-carbonitrile (260 mg, 60%) as an off-white powder: 6 H (360 MHz, CDCl 3 ) 6.97 (1H, dd, J 7 and 4), 7.51 (1H, td, J 1 and 8), 7.59 (iH, 20 dd, J7 and 1), 7.62-7.73 (4H, in), 7.77-7.78 (1H, in), 7.82 (1H, dd, J8 and 1), 7.96 (1H, s), 8.60 (1H, dd, J 7 and 2), 8.98 (1H, d, J 7 and 2); m/z (ES+) 297 (M++H). EXAMPLE 3 25 3'-(7-Trifluoromethylimidazor,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile A mixture of 2-amino-4-(trifluoromethyl)pyrimidine (prepared according to Zanatta et al. in J. Heterocyclic Chen., 1997, 34(2), 509-513) (500 mg, 3.1 mmol) and bromoacetaldehyde diethyl acetal (1.38 ml, 9.2 30 mmol) in ethanol (10 ml) was treated with hydrobromic acid (0.5 ml of a 48% aqueous solution) and then heated at 70'C for 12 h. The reaction was WO 01/90108 PCT/GBO1/02158 - 40 cooled to ambient temperature then pre-adsorbed onto silica. Purification by chromatography on silica eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) afforded 7 trifluoromethylimidazo[1,2-a]pyrimidine (500 mg, 87%) as a cream 5 coloured solid: 5H (400 MHz, CDCl 3 ) 7.22 (1H, d, J 7), 7.74 (1H, d, J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7). 7-Trifluoromethylimidazo[1,2-a]pyrimidine (0.20 g, 1.07 mmol) was brominated as described in Example 1 to give 3-bromo-7 trifluoromethylimidazo[1,2-a]pyrimidine (0.28 g, 98%) as a white solid: 8H 10 (400 MHz, CDCls) 7.35 (1H, d, J 7), 8.02 (1H, s), 8.62 (1H, d, J 7). 3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.28 g, 1.04 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7 trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (165 15 mg, 44%) as a yellow powder: 6 H (400 MHz, CDCl 3 ) 7.29 (1H, d, J 7), 7.53 (1H, td, J8 and 1), 7.59-7.68 (3H, in), 7.70-7.75 (2H, in), 7.80-7.85 (2H, in), 8.14 (1H, s), 9.20 (1H, d, J 7); m/z (ES+) 365 (M++H). EXAMPLE 4 20 3'-[7-(1,1-Dimethoxvethyl)imidazo[1,2-alpyrimidin-3-vllbiphenvl-2 carbonitrile Boron trifluoride etherate (17.03 g, 120.0 mmol) was added drop wise over 15 min to a cooled (-40'C) solution of triethyl orthoformate 25 (14.82 g, 100.0 mmol) in dichloromethane (50 ml). Stirring was continued for 10 min then the solution was transferred to an ice-water bath and stirred at 0 0 C for 20 min. The mixture was cooled to -78*C, and 3,3 dimethoxy-2-butanone (6.61 g, 50.0 mmol) added followed by dropwise addition of NN-diisopropylethylamine (19.39 g, 150.0 mmol) over 15 min. 30 Stirring was continued for 1 h then the solution was poured onto a vigorously stirred mixture of saturated sodium hydrogencarbonate WO 01/90108 PCT/GBO1/02158 - 41 solution (500 ml) and dichloromethane (200 ml). The organic phase was separated, washed with ice-cold IM sulfuric acid solution (2 x 500 ml) and ice-cold water (2 x 500 ml), dried over anhydrous sodium sulfate solution and evaporated to give 1,1 -diethoxy-4,4-dimethoxypentan- 3-one (11.72 g, 5 100%) as an orange oil. 1,1-Diethoxy-4,4-dimethoxypentan-3-one was condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 7-(1,1 dimethoxyethyl)imidazo[1,2-a]pyrimidine (6.61 g, 64%) as a white solid: 6 H (400 MHz, CDC1 3 ) 1.70 (3H, s), 3.28 (6H, s), 7.30 (1H, d, J 7), 7.55 (1H, d, J 10 1), 7.84 (1H, d, J 1), 8.43 (1H, d, J 7). 7-(1,1-Dimethoxyethyl)imidazo[1,2-a]pyrimidine (207 mg, 1.00 mmol) was brominated as described in Example 1 to give 3-bromo-7-(1, 1 dimethoxyethyl)imidazo[1,2-a]pyrimidine (197 mg, 69%) as a white solid: 8H (360 MHz, CDCl 3 ) 1.70 (3H, s), 3.28 (6H, s), 7.43 (1H, d, J 7), 7.82 (1H, 15 s), 8.39 (1H, d, J 7). 3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidine (197 mg, 0.50 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-[7-(1,1 dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (200 20 mg, 76%) as a white powder: SH (360 MHz, CDCl 3 ) 1.72 (3H, s), 3.30 (6H, s), 7.39 (1H, d, J 7), 7.49-7.73 (6H, m), 7.78-7.84 (2H, m), 7.97 (1H, s), 8.95 (iH, d, J 7); in/z (ES+) 385 (M++H). EXAMPLE 5 25 3'-(7-Acetylimidazo[1,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile A solution of 3'-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3 yl]biphenyl-2-carbonitrile (100 mg, 0.26 mmol) in 2.5N hydrochloric acid (4 ml) was heated at 50*C for 15 h. The mixture was cooled, layered with 30 ethyl acetate (5 ml) and made basic (pH 8) with portionwise addition of solid sodium hydrogencarbonate over 15 min. The mixture was diluted WO 01/90108 PCT/GBO1/02158 - 42 with water (5 ml) and extracted with dichloromethane (5 x 30 ml). The combined organics were dried over anhydrous sodium sulfate, filtered, evaporated to dryness and triturated with diethyl ether to give 3'-(7 acetylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (62 mg, 70%) as 5 a yellow solid: 8H (360 MHz, CDCl 3 ) 2.84 (3H, s), 7.26 (1H, d, J 7), 7.52 (1H, td, J8 and 1), 7.58-7.72 (5H, m), 7.80-7.84 (2H, m), 8.16 (1H, s), 9.03 (1H, d, J 7); m/z (ES+) 339 (M++H). EXAMPLE 6 10 3'-(7-Isopropylimidazor,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile 3-Methylbutan-2-one was converted to 1,1-diethoxy-4 methylpentan-3-one as described in Example 4 and condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 7 15 isopropylimidazo[1,2-a]pyrimidine as an orange solid: 8H (400 MHz, CDCls) 1.36 (6H, d, J 7), 3.12 (1H, septet, J 7), 6.78 (1H, d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7). 7-Isopropylimidazo[1,2-a]pyrimidine was brominated as described in Example 1 to give 3-bromo-7-isopropylimidazo[1,2-a]pyrimidine as a 20 cream-coloured solid: 8H (400 MHz, CDC1 3 ) 1.37 (6H, d, J 7), 3.16 (1H, septet, J 7), 6.91 (1H, d, J 7), 7.71 (1H, s), 8.30 (1H, d, J 7). 3-Bromo-7-isopropylimidazo[1,2-a]pyrimidine was coupled with 3' (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7-isopropylimidazo[1,2-a]pyrimidin-3 25 yl)biphenyl-2-carbonitrile as a white powder: Found C, 76.71; H, 5.17; N 16.24. C 22
H
1 8
N
4 .0.3(H 2 0) requires C, 76.59; H, 5.43; N, 16.24; 5H (400 MHz, CDCls) 1.38 (6H, d, J7), 3.16 (1H, septet, J7), 6.88 (1H, d, J7), 7.48-7.76 (7H, m), 7.82 (1H, dd, J8 and 1), 7.85 (1H, s), 8.85 (1H, d, J7); in/z (ES+) 339 (M++H). 30 WO 01/90108 PCT/GBO1/02158 - 43 EXAMPLE 7 3'-(7-Cyclopropylimidazo[1,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile Cyclopropyl methyl ketone was converted to 1-cyclopropyl-3,3 5 diethoxypropan-1-one as described in Example 4 and condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 7 cyclopropylimidazo[1,2-a]pyrimidine as an orange solid: SH (400 MHz, CDCl 3 ) 1.06-1.11 (2H, in), 1.26-1.31 (2H, in), 2.03-2.08 (1H, m), 6.74 (1H, d, J 7), 7.40 (1H, d, J 1), 7.65 (1H, d, J 1), 8.24 (1H, d, J 7). 10 7-Cyclopropylimidazo[1,2-a]pyrimidine was brominated as described in Example 1 to give 3-bromo-7-cyclopropylimidazo[1,2-a]pyrimidine as a tan solid: 8H ( 4 0 0 MHz, CDCl 3 ) 1.10-1.15 (2H, in), 1.29-1.32 (2H, in), 2.04 2.12 (1H, in), 6.88 (1H, d, J 7), 7.63 (1H, s), 8.20 (1H, d, J 7). 3-Bromo-7-cyclopropylimidazo[1,2-a]pyrimidine was coupled with 3' 15 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7-cyclopropylimidazo[1,2-a]pyrimidin-3 yl)biphenyl-2-carbonitrile. Hydrochloride salt, white powder (from acetonitrile): 8H (400 MHz, DMSO) 1.21-1.25 (2H, in), 1.31-1.36 (2H, in), 2.46-2.52 (1H, in), 7.58 (1H, d, J 7), 7.65 (1H, td, J 7 and 1), 7.77-7.88 (5H, 20 m), 7.93-7.94 (1H, in), 8.01 (1H, dd, J7 and 1), 8.37 (1H, s), 9.16 (1H, d, J 7); m/z (ES+) 337 (M++H). EXAMPLE 8 25 3'-(7-tert-Butylimidazo[1,2-alpyrimidin-3-vl)biphenyl-2-carbonitrile 3,3-Dimethylbutan-2-one was converted to 1,1-diethoxy-4,4 dimethylpentan-3-one as described in Example 4 and condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 7-tert butylimidazo[1,2-a]pyrimidine as a pale-orange solid: 6 H (400 MHz, CDCl 3 ) 30 1.42 (9H, s), 6.96 (1H, d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7).
WO 01/90108 PCT/GBO1/02158 - 44 7-tert-Butylimidazo[1,2-a]pyrimidine was brominated as described in Example 1 to give 3-bromo-7-tert-butylimidazo[1,2-a]pyrimidine as an off-white solid: 8H (400 MHz, CD C1 3 ) 1.43 (9H, s), 7.09 (1H, d, J 7), 7.71 (1H, s), 8.30 (1H, d, J 7). 5 3-Bromo-7-tert-butylimidazo[1,2-a]pyrimidine was coupled with 3' (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7-tert-butylimidazo[1,2-a]pyrimidin-3 yl)biphenyl-2-carbonitrile as an off-white powder: Found C, 77.17; H, 5.79; N, 15.78. C 2 3
H
2 0
N
4 .0.3(H 2 0) requires C, 77.21; H, 5.80; N, 15.66; SH (400 10 MHz, CD Cl 3 ) 1.44 (9H, s), 7.05 (1H, d, J 7), 7.48-7.76 (7H, in), 7.83 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.88 (1H, d, J 7); n/z (ES+) 353 (M++H). EXAMPLE 9 15 3'-(7-Cyclobutylimidazo[1,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile Cyclobutyl methyl ketone was converted to 1-cyclobutyl-3,3 diethoxypropan-1-one as described in Example 4 and condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 7 cyclobutylimidazo[1,2-a]pyrimidine as an orange solid: 6 H (400 MHz, 20 CDCla) 1.90-2.55 (6H, m), 3.71 (1H, quintet, J 8), 6.73 (1H, d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.30 (1H, dd, J 7 and 3). 7-Cyclobutylimidazo[1,2-a]pyrimidine was brominated as described in Example 1 to give 3-bromo-7-cyclobutylimidazo[1,2-a]pyrimidine as a cream-coloured solid: 8H (400 MHz, CDCl 3 ) 1.90-2.55 (6H, in), 3.74 (1H, 25 quintet, J8), 6.85 (1H, d, J7), 7.71 (1H, s), 8.27 (1H, d, J7). 3-Bromo-7-cyclobutylimidazo[1,2-a]pyrimidine was coupled with 3' (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7-cyclobutylimidazo[1,2-a]pyrimidin-3 yl)biphenyl-2-carbonitrile as a white powder: 8H (400 MHz, CDCla) 1.90 30 2.55 (6H, in), 3.77 (1H, quintet, J8), 6.83 (1H, d, J7), 7.48-7.75 (7H, in), WO 01/90108 PCT/GBO1/02158 - 45 7.82 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.85 (1H, d, J 7); m/z (ES+) 351 (M++H). EXAMPLE 10 5 3'-(7-Methoxvimidazo[1,2-alpyrimidin-3-vl)biphenyl-2-carbonitrile 2-Amino-4-chloropyrimidine (1.00 g, 7.72 mmol) and sodium methoxide (1.25 g, 23.2 mmol) were suspended in methanol (20 ml) and heated under reflux for 2 h then cooled to ambient temperature. 10 Chloroacetaldehyde (2.4 ml of a 45% w/w solution in water, 15.44 mmol) was added and the mixture heated under reflux for 22 h, allowed to cool to ambient temperature then pre-adsorbed directly onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-4%) gave 7 15 methoxyimidazo[1,2-a]pyrimidine (0.77 g, 67%) as a white crystalline solid: 6 H (400 MHz, CDCl 3 ) 4.04 (3H, s), 6.41 (1H, d, J 7), 7.31 (1H, d, J 1), 7.50 (1H, d, J 1), 8.17 (1H, d, J 7). 7-Methoxyimidazo[1,2-a]pyrimidine (0.66 g, 4.43 mmol) was brominated as described in Example 1 to give 3-bromo-7 20 methoxyimidazo[1,2-a]pyrimidine (0.48 g, 48%) as an off-white solid: 8H (360 MHz, CDCl 3 ) 4.06 (3H, s), 6.53 (1H, d, J 7), 7.48 (1H, s), 8.14 (1H, d, J 7). 3-Bromo-7-methoxfimidazo[1,2-a]pyrimidine (0.48 g, 2.12 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl 25 2-carbonitrile as described in Example 1 to give 3'-(7-methoxyimidazo[1,2 a]pyrimidin-3-yl)biphenyl-2-carbonitrile (458 mg, 66%) as a white powder: 8H (400 MHz, CDCl 3 ) 4.08 (3H, s), 6.49 (1H, d, J 7), 7.50 (1H, td, J 8 and 1), 7.51-7.71 (8H, in), 7.81 (1H, dd, J8 and 1), 8.66 (1H, d, J 7); m/z (ES+) 327 (M++H). 30 WO 01/90108 PCT/GBO1/02158 - 46 EXAMPLE 11 3'-(7-Hydroxymethylimidazo[1,2-alpyrimidin-3-yl)biphenvl-2-carbonitrile Pyruvic aldehyde dimethyl acetal (8.43 g, 71.4 mmol) and NN 5 dimethylformamide dimethyl acetal (8.51 g, 71.4 mmol) were heated at 100'C for 18 h. The mixture was concentrated to give a brown oil and was then added dropwise over 10 min to a warm (60 0 C) suspension of 2 aminoimidazole hemisulfate (9.43 g, 71.4 mmol) in water (50 ml). The mixture was heated at 50'C for 36 h, cooled to ambient temperature and 10 then pre-adsorbed directly onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-2%) gave a 3:1 mixture of 7 dimethoxymethylimidazo[1,2-a]pyrimidine and 5 dimethoxymethylimidazo[1,2-a]pyrimidine respectively. Crystallisation 15 from toluene gave 7-dimethoxymethylimidazo[1,2-a]pyrimidine (2.20 g, 16%) as a brown crystalline solid: 6 H (400 MHz, CDCl 3 ) 3.50 (6H, s), 5.26 (1H, s), 7.15 (1H, d, J 7), 7.56 (1H, d, J 1), 7.84 (1H, d, J 1), 8.47 (1H, d, J 7). 7-Dimethoxymethylimidazo[1,2-a]pyrimidine (1.00 g, 5.18 mmol) 20 was dissolved in 3N hydrochloric acid and heated at 48 0 C for 14 h. The solution was layered with ethyl acetate (30 ml) and solid sodium hydrogencarbonate (1.06 g, 12.6 mmol) was added in portions over 5 min. The mixture was diluted with water (6 ml) and extracted with dichloromethane (5 x 50 ml). The combined organics were dried over 25 anhydrous sodium sulfate, filtered and evaporated to give imidazo[1,2 a]pyrimidine-7-carbaldehyde (749 mg, 99%) as a yellow solid: 5H (360 MHz, CDCl 3 ) 7.53 (1H, d, J7), 7.77 (1H, d, J1), 8.10 (1H, d, J1), 8.60 (1H, d, J 7), 10.05 (1H, s). Sodium triacetoxyborohydride (21.5 g, 102 mmol) was added 30 portionwise over 20 min to a stirred solution of imidazo[1,2-a]pyrimidine 7-carbaldehyde (5.00 g, 34.0 mmol) in methanol (100 ml) and the solution WO 01/90108 PCT/GBO1/02158 - 47 left to stir at ambient temperature for 18 h. The solvent was evaporated, the residue redissolved in methanol (150 ml) and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-10%) gave 5 imidazo[1,2-a]pyrimidin-7-ylmethanol (5.06 g, 99%) as a white solid: 8H (360 MHz, DMSO) 4.57 (2H, d, J6), 5.62 (1H, t, J6), 7.13 (1H, d, J7), 7.64 (1H, d, J 1), 7.86 (1H, d, J 1), 8.94 (1H, d, J 7). Imidazo[1,2-a]pyrimidin-7-ylmethanol (1.70 g, 11.4 mmol) was brominated as described in Example 1 to give 3-bromoimidazo[1,2 10 a]pyrimidin-7-ylmethanol (912 mg, 35%) as a white solid: 8H (400 MHz, CDCl 3 ) 2.95 (1H, br), 4.88 (2H, s), 7.03 (1H, d, J7), 7.73 (1H, s), 8.37 (1H, d, J 7). 3-Bromoimidazo[1,2-a]pyrimidin-7-ylmethanol (912 mg, 4.00 mmol) was dissolved in dichloromethane (10 ml) and treated with imidazole (0.70 15 g, 10.3 mmol) and tert-butyldimethylsilyl chloride (0.77 g, 5.1 mmol) and the mixture left to stir at ambient temperature for 1 h. The reaction was diluted with dichloromethane (75 ml) and washed with 0.O1N hydrochloric acid (2 x 50 ml). The organic phase was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried 20 over anhydrous magnesium sulfate, filtered and evaporated to give crude 3-bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidine (1.37 g, 100%) as a yellow solid. 3-Bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2 a]pyrimidine (1.37 g, 4.00 mmol) was coupled with 3'-(4,4,5,5-tetramethyl 25 [1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-[7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidin 3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in methanol (25 ml) and treated with conc. hydrochloric acid (1 ml) and left to stir at ambient temperature for 5 min. The solution was loaded onto a 30 cartridge of strong cation-exchange resin, eluting with methanol then with 10% conc. ammonia in methanol. The basic fractions were concentrated in WO 01/90108 PCT/GBO1/02158 -48 vacuo and the residue purified further by chromatography on silica gel. Elution with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (2-5%) afforded 3'-(7-hydroxymethylimidazo[1,2 a]pyrimidin-3-yl)biphenyl-2-carbonitrile (587 mg, 45%) as a yellow powder: 5 6H (400 MHz, CDCl 3 ) 1.90 (1H, s), 4.88 (2H, s), 6.91 (1H, d, J 7), 7.51 (1H, td, J 8 and 1), 7.57-7.73 (5H, in), 7.77 (1H, dd, J 1 and 1), 7.82 (1H, dd, J 8 and 1), 7.89 (1H, s), 8.94 (1H, d, J 7); in/z (ES+) 327 (M++H). EXAMPLE 12 10 3'-(7-Fluoromethylimidazor,2-alpyrimidin-3-yl)biphenyl-2-carbonitrile To a cooled (-78'C) suspension of 3'-(7-hydroxymethylimidazo[1,2 a]pyrimidin-3-yl)biphenyl-2-carbonitrile (75 mg, 0.23 mmol) in dichloromethane (20 ml) was added (diethylamino)sulfur trifluoride (39 15 mg, 0.24 mmol) dropwise over 5 min. The mixture was stirred at -78 0 C for 20 min then allowed to warm to -40'C for 5 min before quenching the reaction with a pre-cooled (-40 0 C) solution of acetic acid (0.5 ml) in dichloromethane (5 ml). The mixture was warmed to ambient temperature, made basic with saturated sodium hydrogencarbonate 20 solution (30 ml) and extracted with dichloromethane (2 x 50 ml). The combined organics were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification of this material by preparative thin-layer chromatography eluting with dichloromethane/methanol/conc. ammonia (96:4:0.4) gave a solid which 25 was triturated with diethyl ether to give 3'-(7-fluoromethylimidazo[1,2 a]pyrimidin-3-yl)biphenyl-2-carbonitrile (8 mg, 11%) as a yellow powder: 8H (360 MHz, CDCl 3 ) 5.57 (2H, d, J 47), 7.20 (1H, dd, J 7 and 2), 7.52 (iH, dt, J8 and 1), 7.58-7.74 (5H, m), 7.78-7.79 (1H, m), 7.83 (1H, d, J8), 7.95 (1H, s), 9.03 (1H, dd, J 7 and 1); m/z (ES+) 329 (M++H). 30 WO 01/90108 PCT/GBO1/02158 - 49 EXAMPLE 13 3'-(7-Formylimidazo[1,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile 3'-(7-Hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 5 carbonitrile (20 mg, 0.061 mmol) and manganese(IV) oxide (53 mg, 0.61 mmol) were suspended in 1,2-dichloroethane (2 ml) and heated at 50*C for 18 h. The mixture was filtered through Celite and the filtrate concentrated in vacuo. Purification of the residue by preparative thin layer chromatography eluting with dichloromethane/methanol/conc. 10 ammonia (96:3:0.3) gave a solid which was triturated with diethyl ether to give 3'-(7-formylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (10 mg, 50%) as a yellow powder: 8H (360 MHz, DMSO) 7.48 (1H, d, J 7), 7.64 (1H, td, J8 and 1), 7.70-7.92 (5H, in), 7.95-8.05 (2H, in), 8.42 (1H, s), 9.32 (1H, d, J 7), 9.96 (1H, s); n/z (ES+) 325 (M++H). 15 EXAMPLE 14 3'-(7-Hydroxviminomethylimidazor,2-alpyrimidin-3-vl)biphenvl-2 carbonitrile 20 3'-(7-Formylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg, 0.31 mmol) and 50% aqueous hydroxylamine (127 mg, 1.54 mmol) were dissolved in ethanol (2 ml) and the mixture heated at 40'C for 1 h. Purification of the reaction mixture by preparative thin-layer chromatography eluting with dichloromethane/methanol/conc. ammonia 25 (96:4:0.4) gave a solid which was triturated with diethyl ether to give 3'-(7 hydroxyiminomethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (70 mg, 67%) as a white powder: 6 H (400 MHz, DMSO) 7.42 (1H, d, J 7), 7.61-7.80 (5H, in), 7.82-7.86 (2H, in), 7.94 (1H, dd, J 1 and 1), 8.00 (1H, dd, J8 and 1), 8.10 (1H, d, J8), 9.09 (1H, d, J7), 12.20 (1H, s); m/z (ES+) 340 30 (M++H).
WO 01/90108 PCT/GBO1/02158 - 50 EXAMPLE 15 3-(2'-Cyanobiphenvil-3-vl)imidazo[1,2-alpyrimidine-7-carbonitrile 3'-(7-Hydroxyiminomethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 5 carbonitrile (60 mg, 0.177 mmol) and 1,1'-carbonyldiimidazole (143 mg, 0.88 mmol) were suspended in dichloromethane (2 ml) and triethylamine (89 mg, 0.88 mmol) was added dropwise over 5 min. Stirring was continued for 15 min then the mixture was heated under reflux for 90 min. Purification of the reaction mixture by preparative thin-layer 10 chromatography eluting with dichloromethane/methanol/conc. ammonia (98:2:0.2) gave a solid which was triturated with diethyl ether to give 3-(2' cyanobiphenyl-3-yl)imidazo[1,2-a]pyrimidine-7-carbonitrile (56 mg, 97%) as a white powder: SH (400 MHz, CDCla) 7.26 (1H, d, J 7), 7.53 (1H, td, J 8 and 1), 7.59-7.67 (3H, m), 7.70-7.76 (2H, in), 7.81-7.85 (2H, in), 8.24 (1H, 15 s), 9.16 (1H, d, J 7); m/z (ES+) 322 (M++H). EXAMPLE 16 3-(2'-Methoxvbiphenvl-3-vl)-7-methylimidazo[1,2-alpyrimidine 20 A mixture of 3-bromo-7-methylimidazo[1,2-a]pyrimidine (5.3 g, 25 mmol), 3-methoxyphenylboronic acid (4.94 g, 32.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.8 mmol) in 1,2 dimethoxyethane (40 ml) was treated with sodium carbonate (18.8 ml of a 2M aqueous solution) then heated at 85 0 C for 16 h. The reaction mixture 25 was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The organics were washed with 10% sodium carbonate solution, water, brine, dried over anhydrous magnesium sulfate, filtered then pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane:conc. ammonia (99.5:0.5) on a 30 gradient of methanol (1-3%) afforded 3-(3-methoxyphenyl)-7 methylimidazo[1,2-a]pyrimidine as a cream-coloured solid (5.3 g, 89%): 8H WO 01/90108 PCT/GBO1/02158 - 51 (400 MHz, CDCl 3 ) 2.66 (3H, s), 3.87 (3H, s), 6.76 (1H, d, J 7), 6.95-6.98 (1H, in), 7.03-7.05 (1H, m), 7.09-7.11 (1H, in), 7.44 (1H, t, J8), 7.80 (1H, s), 8.52 (1H, d, J 7); in/z (ES+) 240 (M++H). A mixture of 3-(3-methoxyphenyl)-7-methylimidazo[1,2 5 a]pyrimidine (5.02 g, 21 mmol) in hydrogen bromide (25 ml of a 30 wt. % solution in acetic acid) was heated at 130'C for 8 h. A further portion of hydrogen bromide solution was added (25 ml) and heating continued for 16 h. The reaction was cooled to ambient temperature and diluted with ice cold water (200 ml). The aqueous phase was made neutral with 4N 10 sodium hydroxide then extracted with dichloromethane (2 x 250 ml). The organics were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with ether to afford 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl) phenol as a light-grey solid (4.4 g, 93%): m/z (ES+) 226 (M++H). 15 A cooled (-10*C) suspension of 3-(7-methylimidazo[1,2-a]pyrimidin 3-yl)phenol (4.28 g, 19 mmol) in dichloromethane (75 ml) was treated with pyridine (2.46 ml, 30 mmol) then with trifluoromethanesulfonic anhydride (4.05 ml, 25 mmol) added dropwise over 15 min. The resulting dark solution was stirred at -10 0 C for 30 min then warmed to ambient 20 temperature. The reaction was diluted with dichloromethane (200 ml) then extracted with 0. IN hydrochloric acid (2 x 200ml), water, brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford crude trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2 a]pyrimidin-3-yl)phenyl ester as a dark oil: in/z (ES+) 316 (M++H). This oil 25 was dissolved in NN-dimethylacetamide (50 ml) and degassed with nitrogen for 30 min before adding potassium phosphate (8.1 g, 38 mmol), tetrakis(triphenylphosphine)palladium(0) (660 mg, 0.6 mmol) and 2 methoxyphenylboronic acid (4.62 g, 30.4 mmol). This reaction mixture was then heated at 80'C for 12 h, allowed to cool to ambient temperature 30 then partitioned between ethyl acetate and water. The organics were washed with 0. IN sodium hydroxide, water, brine, dried over anhydrous WO 01/90108 PCT/GBO1/02158 - 52 magnesium sulfate, filtered then pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane:conc. ammonia (99.5:0.5) on a gradient of MeOH (1-4%) afforded 3-(2'-methoxybiphenyl-3 yl)-7-methylimidazo[1,2-a]pyrimidine as a pale yellow solid (4.4 g, 73%): 8H 5 (400 MHz, DMSO) 2.58 (3H, s), 3.82 (3H, s), 7.03-7.08 (2H, in), 7.16 (1H, d, J8), 7.38-7.45 (2H, in), 7.53-7.65 (3H, in), 7.74 (1H, s), 7.89 (1H, s), 8.91 (1H, d, J 8); mn/z (ES+) 316 (M++H). EXAMPLE 17 10 3-(2'-Cyanobiphenyl-3-vl)imidazor,2-alpyrimidine-7-carboxylic acid methyl ester 4-Ethoxy-2-oxobut-3-enoic acid methyl ester was condensed with 2 aminoimidazole hemisulfate as described in Example 1 to give 15 imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester as an orange solid: 5H (400 MHz, CDCl 3 ) 4.05 (3H, s), 7.68 (1H, d, J 7), 7.72 (1H, d, J 1), 8.06 (1H, d, J 1), 8.59 (1H, d, J 7). Imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester was brominated as described in Example 1 to give 3-bromoimidazo[1,2 20 a]pyrimidine-7-carboxylic acid methyl ester as a cream-coloured solid: 6 H (400 MHz, CDCls) 4.07 (3H, s), 7.80 (1H, d, J 7), 8.04 (1H, s), 8.55 (iH, d, J7). 3-Bromoimidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl 25 2-carbonitrile as described in Example 1 to give 3-(2'-cyanobiphenyl-3-yl) imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester as a pale yellow powder: 8H (400 MHz, CDCls) 4.07 (3H, s), 7.50-7.54 (1H, in), 7.58-7.76 (6H, in), 7.81-7.84 (2H, in), 8.18 (1H, s), 9.10 (1H, d, J 7); in/z (ES+) 355 (M++H).
WO 01/90108 PCT/GBO1/02158 - 53 EXAMPLE 18 3'-(7-Dimethoxvmethylimidazo[1,2-alpvrimidin-3-vl)biphenyl-2 carbonitrile 5 7-Dimethoxymethylimidazo[1,2-a]pyrimidine was brominated as described in Example 1 to give 3-bromo-7-dimethoxymethylimidazo[1,2 a]pyrimidine as an off-white solid: 5H (400 MHz, CDCl 3 ) 3.50 (6H, s), 5.28 (1H, s), 7.28 (1H, d, J 7), 7.81 (1H, s), 8.43 (1H, d, J 7); n/z (ES+) 272/274 (M++H). 10 3-Bromo-7-dimethoxymethylimidazo[1,2-a]pyrimidine (0.28 g, 1.04 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7 dimethoxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (165 mg, 44%) as a yellow powder: 8H (400 MHz, CDCl 3 ) 3.51 (6H, s), 5.30 (1H, 15 s), 7.25 (1H, d, J7), 7.51 (1H, td, J8 and 1), 7.57-7.70 (5H, in), 7.76-7.77 (1H, in), 7.82 (1H, dd, J 8 and 1), 7.96 (1H, s), 8.97 (1H, d, J 7); m/z (ES+) 371 (M++H). EXAMPLE 19 20 3'-[7-([1,2,4lTriazol-1-vlmethyl)imidazo[1,2-alpvrimidin-3-vllbiphenvl-2 carbonitrile To a solution of 3'-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl) biphenyl-2-carbonitrile (0.1 g, 0.31 mmol) in dichloromethane (5 ml) was 25 added carbon tetrabromide (153 mg, 0.46 mmol) and triphenylphosphine (121 mg, 0.46 mmol). This mixture was stirred at ambient temperature for 6 h after which time 1,2,4-triazole sodium salt (84 mg, 0.93 mmol) was added and the reaction stirred at ambient temperature for a further 18 h. The solvent was removed in vacuo and the residue purified by silica gel 30 chromatography eluting with dichloromethane on a gradient of methanol (0-10%). Further purification by high performance liquid chromatography WO 01/90108 PCT/GBO1/02158 - 54 gave 3'-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl 2-carbonitrile (15.3 mg): 8H (400 MHz, DMSO) 5.76 (2H, s), 7.32 (1H, d, J 7), 7.52-7.84 (8H, in), 8.16 (2H, d, J 5), 8.73 (1H, s), 9.22 (1H, s); n/z (ES+) 378 (1M++H). 5 EXAMPLE 20 3'-(7-Difluoromethylimidazo[1,2-alpvrimidin-3-vl)biphenvl-2-carbonitrile 4-Ethoxy- 1, 1-difluorobut-3-en-2-one was condensed with 2 10 aminoimidazole hemisulfate using the procedure described in Example 1 to give 7-difluoromethylimidazo[1,2-a]pyrimidine (16.9 g, 46%) as a pale brown crystalline solid: 8H (400 MHz, CDCl 3 ) 6.64 (1H, t, J 55), 7.26 (1H, d, J 7), 7.67 (1H, d, J 1), 7.95 (1H, d, J 1), 8.60 (1H, d, J 7). 7-Difluoromethylimidazo[1,2-a]pyrimidine (1.00 g, 5.91 mmol) was 15 brominated as described in Example 1 to give 3-bromo-7 difluoromethylimidazo[1,2-a]pyrimidine (0.95 g, 65%) as a white solid: 8H (400 MHz, CDCl 3 ) 6.67 (1H, t, J 55), 7.34 (1H, d, J 7), 7.94 (1H, s), 8.57 (1H, d, J7). 3-Bromo-7-difluoromethylimidazo[1,2-a]pyrimidine (248 mg, 1.00 20 mmol) was coupled with 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 yl)biphenyl-2-carbonitrile as described in Example 1 to give 3'-(7 difluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (201 mg, 58%) as a yellow powder: 8H (400 MHz, CDCls) 6.67 (1H, t, J 55), 7.29 (1H, d, J 7), 7.52 (1H, td, J 9 and 1), 7.58-7.74 (5H, in), 7.87 (2H, m), 8.01 25 (1H, s), 9.12 (1H, d, J 7); m/z (ES+) 347 (M++H). EXAMPLE 21 7-Methyl-3-[3- (pyridin-3-vl)phenvllimidazo[1,2-alpyrimidine 30 To a degassed solution of trifluoromethanesulfonic acid 3-(7-methyl imidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) in 1,4-dioxane WO 01/90108 PCT/GBO1/02158 - 55 (3 ml) was added potassium phosphate (0.119 g, 0.56 mmol), pyridine-3 boronic acid 1,3-propanediol cyclic ester (0.092 g, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 13.8 pLmol) and the mixture heated at 80 0 C for 22 h. After cooling to ambient temperature the 5 solvent was evaporated in vacuo. The residue was stirred with 10% methanol in dichloromethane and the solid material filtered off. The filtrate was applied to two preparative TLC plates (silica gel) and eluted with 6% methanol in dichloromethane. The appropriate band was collected and processed to give an oil which crystallised from diethyl ether 10 as a white solid (26 Ing): 8H (400 MHz, CDCls) 2.67 (3H, s), 6.80 (1H, d, J 7), 7.42 (1H, td, J8 and 1), 7.57 (1H, in), 7.65 (2H, in), 7.71 (1H, s), 7.86 (1H, s), 7.92 (1H, in), 8.53 (1H, d, J 7), 7.65 (1H, m), 8.89 (1H, s); in/z (ES+) 287 (M++H). 15 EXAMPLE 22 7-Methyl-3-[3'-(5-methyl-ri,2,41oxadiazol-3-vl)biphenyl-3-Vllimidazo[1,2 alpyrimidine To a degassed solution of trifluoromethanesulfonic acid 3-(7-methyl 20 imidazo[1,2-a]pyrimidin-3-yl)phenyl ester (2.53 g, 7 mmol) in 1,4-dioxane (25 ml) was added potassium acetate (2.08 g, 21 mmol), bis(pinacolato)diboron (1.97 g, 7.8 mmol) and dichloro[1,1' bis(diphenylphosphino)ferrocene]palladium(H) (0.258 g, 0.35 mmol) and the mixture heated at 80*C for 22 h. After cooling to ambient temperature 25 the reaction was poured into water, extracted with ethyl acetate (3 x 100 ml) and the combined organics were dried over magnesium sulfate. Filtration and evaporation in vacuo gave a dark oil which was chromatographed on silica gel, eluting with a gradient of 1 to 10% methanol in dichloromethane. Appropriate fractions were pooled and 30 evaporated to give 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan 2-yl)phenyl]imidazo[1,2-a]pyrimidine as a cream coloured solid (1.97 g): SH WO 01/90108 PCT/GBO1/02158 - 56 (400 MHz, CDCls) 1.36 (12H, s), 6.77 (1H, d, J 7), 7.52 (1H, m), 7.59 (1H, in), 7.80 (1H, s), 7.87 (1H, in), 7.95 (1H, s), 8.50 (1H, d, J 7); m/z (ES+) 336 (M++H). To a degassed solution of 7-methyl-3-[3-(4,4,5,5-tetramethyl 5 [1,3,2] dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) in 1,4-dioxane (3 ml) was added 3-(3-bromophenyl)-5-methyl [1,2,4]oxadiazole (0.142 g, 0.59 mmol) (prepared as described in WO 95/27692), potassium phosphate (189 mg, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 pmol) and the 10 mixture heated at 90'C for 18 h. After cooling to ambient temperature the solvent was evaporated in vacuo and the residue stirred with 10% methanol in dichloromethane. The solid material was removed by filtration and the filtrate applied to two preparative TLC plates (silica gel) and eluted with 5% methanol in dichloromethane. The appropriate band 15 was collected and processed, affording a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 7-methyl-3-[3'-(5 methyl-[1,2,4]oxadiazol-3-yl)biphenyl-3-yl]imidazo[1,2-a]pyrimidine as a cream coloured solid (32 mg): 8H (400 MHz, CDCl 3 ) 2.67 (3H, s), 2.68 (3H, s), 6.79 (1H, d, J 7), 7.60-7.80 (5H, m), 7.87 (1H, s), 7.92 (1H, in), 8.10 (1H, 20 dd, J 7 and 1), 8.32 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 368 (M++H). EXAMPLE 23 7-Methyl-3-[2'-(3-methyl-[1,2,41oxadiazol-5-vl)biphenyl-3-vllimidazo[1,2 25 alpyrimidine To activated molecular sieves (2.0 g, 4A powdered) was added ethanol (20 ml) followed by sodium metal (0.435 g, 18.9 mmol), and the mixture heated at reflux for 15 min. After cooling to ambient temperature, acetamide oxime (1.4 g, 18.9 mmol) was added and the 30 suspension stirred for 15 min. Methyl 2-bromobenzoate (1.32 ml, 9.5 mmol) was added and the mixture heated at reflux for 2 h. The reaction WO 01/90108 PCT/GBO1/02158 - 57 was poured into water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to give a white solid. The crude product was purified by crystallisation from ethyl acetate/isohexane to give 5-(2-bromophenyl)-3 5 methyl-[1,2,4]oxadiazole as a white solid (0.76 g): 6 H (400 MHz, CDCl 3 ) 2.52 (3H, s), 7.45 (2H, m), 7.76 (1H, dd, J7.8 and 1.2), 7.97 (1H, dd, J 7.8 and 1.2); m/z (ES+) 239:241 (1:1) (M++H). 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 5-(2 10 bromophenyl)-3-methyl-[1,2,4]oxadiazole (0.142 g, 0.59 mmol) as described in Example 22 and purified by mass-directed preparative HPLC to give 7 methyl-3-[2'-(3-methyl-[1,2,4]oxadiazol-5-yl)biphenyl-3-yl]imidazo[1,2 a]pyrimidine as its trifluoroacetate salt (21 mg): 5H (400 MHz, CDCl 3 ) 2.40 (3H, s), 2.76 (3H, s), 7.07 (1H, d, J 7), 7.43-7.69 (7H, m), 8.03 (1H, s), 8.10 15 (1H, dd, J7.8 and 1.1), 8.61 (1H, d, J 7); n/z (ES+) 368 (M++H). EXAMPLE 24 7-Methyl-3-[3-(thiazol-4-vl)phenyllimidazo[1,2-alpvrimidine 20 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 4 bromothiazole (98 mg, 0.59 mmol) as described in Example 22 except using NN-dimethylacetamide in place of 1,4-dioxane as solvent. After cooling to ambient temperature the reaction was poured onto a strong 25 cation exchange cartridge and eluted with methanol. The product was then eluted with a 2.OM solution of ammonia in methanol and evaporated in vacuo. The product was purified by mass-directed preparative HPLC to give 7-methyl-3-[3-(thiazol-4-yl)phenyl]imidazo[1,2-a]pyrimidine as its trifluoroacetate salt (24 mg): 8H (400 MHz, CDCl 3 ) 2.77 (3H, s), 7.12 (1H, 30 d, J 7), 7.51 (1H, in), 7.64-7.69 (2H, in), 8.05-8.09 (2H, in), 8.17 (1H, in), 8.65 (1H, d, J 7), 8.92 (1H, s); mn/z (ES+) 293 (M++H).
WO 01/90108 PCT/GBO1/02158 - 58 EXAMPLE 25 3'-(7-Methylimidazo[1,2-alpyrimidin-3-vl)biphenyl-2-carbaldehyde oxime 5 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 2 bromobenzaldehyde oxime (98 mg, 0.59 mmol) as described in Example 24 to give 3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbaldehyde oxime as its trifluoroacetate salt (24 mg): 8H (400 MHz, d6DMSO) 2.71 (3H, 10 s), 7.42-7.53 (4H, d, J 7), 7.68-7.79 (3H, m), 7.89 (1H, m), 8.01 (1H, s), 8.37 (1H, s), 8.65 (1H, d, J 7), 9.17 (1H, d, J 7.1), 11.36 (1H, bs); m/z (ES+) 329 (M++H). EXAMPLE 26 15 3-[3-(7-Methylimidazo[1,2-alpyrimidin-3-yl)phenllpvridine-2-carbonitrile 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 3 bromopyridine-2-carbonitrile (0.11 g, 0.59 mmol) as described in Example 20 24. The crude product was applied to two preparative plates (silica gel) and eluted with 5% methanol in dichloromethane. The appropriate band was collected and processed, affording a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 3-[3-(7 methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile as a 25 white solid (31 mg): 6 H (400 MHz, CDCl 3 ) 2.67 (3H, s), 6.80 (1H, d, J 7), 7.55 (1H, td, J8 and 1), 7.63-7.73 (3H, m), 7.77 (1H, m), 7.86 (1H, s), 7.94 (1H, dd, J 8 and 1.6), 8.75 (1H, d, J 1.6), 8.80 (1H, d, J 7); mn/z (ES+) 312
(M++H).
WO 01/90108 PCT/GBO1/02158 - 59 EXAMPLE 27 7-Methyl-3-[3- (pyridin-2-yl1henvllimidazo[1,2-alpyrimidine 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] 5 imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 2 bromopyridine (55 ptl, 0.59 mmol) as described in Example 26 to give 7 methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine as a white solid (30 mg): 6 H (400 MHz, CDCl 3 ) 2.67 (3H, s), 6.79 (1H, d, J 7), 7.30 (1H, in), 7.55-7.65 (2H, in), 7.77-7.81 (2H, in), 7.87 (1H, s), 8.00 (1H, dd, J8 and 10 1.6), 8.19 (1H, d, J 1.5), 8.57 (1H, d, J 7), 8.71 (1H, d, J1.6); mn/z (ES+) 287 (M++H). EXAMPLE 28 15 7-Methyl-3-[3-(thiazol-2-vl)phenvllimidazo[1,2-alpyrimidine 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 2 bromothiazole (52 pl, 0.59 mmol) as described in Example 26 to give 7 methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine as a white solid 20 (23 mg): 8H (400 MHz, CD C1 3 ) 2.68 (3H, s), 6.81 (1H, d, J 7), 7.39 (1H, d, J 3.2), 7.57-7.63 (2H, in), 7.87 (1H, s), 7.91 (1H, d, J 3.2), 7.99 (1H, dd, J8 and 1.6), 8.17 (1H, in), 8.57 (1H, d, J 7); m/z (ES+) 293 (M++H). EXAMPLE 29 25 7-Methyl-3-(2'-trifluoromethylbiphenyl-3-yl)imidazo[1,2-alpyrimidine Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin 3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2 trifluoromethylbenzeneboronic acid (52 1d, 0.59 mmol) as described in 30 Example 21 to give 7-methyl-3-(2'-trifluoromethylbiphenyl-3-yl) imidazo[1,2-a]pyrimidine as a white solid (35 mg): 5H (400 MHz, CDCl 3
)
WO 01/90108 PCT/GBO1/02158 - 60 2.65 (3H, s), 6.77 (1H, d, J 7), 7.39 (1H, m), 7.48-7.62 (6H, m), 7.78 (1H, d, J7.2), 7.82 (1H, s), 8.52 (1H, d, J7); m/z (ES+) 354 (M++H). EXAMPLE 30 5 3-(2'-Fluorobiphenyl-3-vl)-7-methylimidazo[1,2-alpyrimidine Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin 3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2-fluorobenzene boronic acid (52 pl, 0.59 mmol) as described in Example 21 to give 3-(2' 10 fluorobiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine as a white solid (104 mg): 8H (400 MHz, CDCls) 2.67 (3H, s), 6.78 (1H, d, J 7), 7.17-7.28 (2H, m), 7.37 (1H, m), 7.46-7.54 (2H, m), 7.60 (2H, m), 7.71 (1H, s), 7.85 (1H, s), 8.56 (1H, d, J 7); in/z (ES+) 304 (M++H). 15 EXAMPLE 31 4-Fluoro-3'-(7-methylimidazo[1,2-alpyrimidin-3-vl)biphenvl-2-carbonitrile 7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl] imidazo[1,2-a]pyrimidine (0.2 g, 0.6 mmol) was coupled to 2-bromo-5 20 fluorobenzonitrile (179 mg, 0.9 mmol) as described in Example 26 to give 4-fluoro-3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid (85 mg): 8H (400 MHz, CDCl 3 ) 2.67 (3H, s), 6.83 (1H, d, J 7), 7.20 (1H, dt, J8.9 and 3), 7.50-7.70 (6H, m), 7.84 (1H, s), 8.76 (1H, d, J 7); m/z (ES+) 329 (M++H). 25 EXAMPLE 32 3-r3-(Imidazol-1-vl)phenvll-7-trifluoromethylimidazor,2-alpyrimidine To a cooled (-78'C) solution of 3-bromo-7-trifluoromethyl 30 imidazo[1,2-a]pyrimidine (1.0 g, 3.78 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.08 ml of a 2.OM solution in WO 01/90108 PCT/GBO1/02158 - 61 tetrahydrofuran, 4.16 mmol). After stirring for 5 min tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reaction stirred for 10 min at -78 0 C then allowed to warm to ambient temperature to give a solution of 3 tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine in 5 tetrahydrofuran (ca. 0.15M): m/z (ES+) 474, 476, 478 (M++H). To a degassed solution of 3-tributylstannyl-7-trifluoromethyl imidazo[1,2-a]pyrimidine (1.4 mmol) was added 1-(3-bromophenyl)-1H imidazole (0.60 g, 2.7 mmol) (prepared by the method of A. Johnson et al., J. Med. Chem., 1969, 12(5), 1024-8) and tetrakis(triphenylphosphine) 10 palladium(0) (218 mg, 0.18 mmol) and the mixture heated at reflux for 18 h. The crude reaction was adsorbed onto silica and chromatographed on silica, eluting on a gradient of 1 to 5% methanol in dichloromethane, to give a yellow oil. Crystallisation from ethyl acetate/isohexane afforded 3 [3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.098 15 g) as a white solid: 8H (400 MHz; DMSO) 7.15 (1H, s), 7.53 (1H, d, J 7.4), 7.73 (1H, dd, J 3.1 and 1.6), 7.74 (1H, d, J0.8), 7.78-7.81 (1H, in), 7.89 (1H, t, J 1.4), 8.08 (1H, dd, J 1.6 and 1.2), 8.39 (2H, d, J 7.0), 9.44 (1H, d, J 6.7); m/z (ES+) 330 (M++H). 20 EXAMPLE 33 3-[3-([1,2,41Triazol-1-vl)phenvll-7-trifluoromethylimidazor,2-alpyrimidine A suspension of 3-bromophenylhydrazine hydrochloride (3.78 g, 17 mmol) in formamide (15 ml) was heated at 140'C for 16 h. The reaction 25 mixture was cooled to ambient temperature, diluted into dichloromethane (100 ml) and washed with water (2 x 100 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give 1-(3-bromophenyl)-1H-[1,2,4]triazole (3.44 g) as a tan solid: SH (400 MHz, CDCl 3 ) 8.57 (1H, s), 8.11 (1H, s), 7.90 (1H, t, J2), 7.62-7.64 30 (1H, m), 7.53-7.55 (1H, m), 7.38 (1H, t, J8).
WO 01/90108 PCT/GBO1/02158 - 62 1-(3-Bromophenyl)-1H-[1,2,4]triazole (1.7 g, 7.6 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (3.8 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (1-3%), then 5 crystallisation from toluene/isohexane, gave 3-[3-([1,2,4]triazol-1-yl) phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as an off-white solid: 6H (400 MHz, DMSO) 9.43 (1H, d, J 7), 9.41 (1H, s), 8.38 (1H, s), 8.30 (1H, s), 8.26-8.28 (1H, m), 7.97-8.00 (1H, m), 7.76-7.81 (2H, in), 7.56 (1H, d, J7); m/z (ES+) 331 (M++H). 10 EXAMPLE 34 3-[2'-([1,2,41Triazol-1-Vl)biphenvl-3-vll-7-trifluoromethylimidazo[1,2 alpyrimidine 15 A suspension of 2-bromophenylhydrazine hydrochloride (5.0 g, 22 minol) in formamide (10 ml) was heated at 140'C for 16 h. The reaction mixture was cooled to ambient temperature, diluted into dichloromethane (50 ml) and washed with water (3 x 20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. 20 Purification by chromatography on silica gel eluting with dichloromethane gave 1-(2-bromophenyl)-1H-[1,2,4]triazole (4.80 g) as a tan solid: 6H (400 MHz, CDCl 3 ) 8.49 (1H, s), 8.14 (1H, s), 7.76 (1H, dd, J 1 and 8), 7.44-7.53 (2H, in), 7.34-7.39 (1H, m). To a degassed solution of 1-(2-bromophenyl)-1H-[1,2,4]triazole (1.0 25 g, 4.5 mmol) in toluene (50 ml) was added hexabutylditin (4.7 ml, 9.3 mmol), then tetrakis(triphenylphosphine)palladium(0) (160 ing, 139 .mol) and the reaction heated at reflux for 48 h. The solvent was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with dichloromethane to give 1-(2-tributylstannylphenyl)-1H 30 [1,2,4]triazole as an oil: in/z (ES+) 434, 435, 436 (M++H).
WO 01/90108 PCT/GBO1/02158 - 63 To a degassed solution of 1-(2-tributylstannylphenyl)-1H [1,2,4]triazole (300 mg, 0.7 mmol) in NN-dimethylformamide (5 ml) was added 1,3-dibromobenzene (0.17 ml, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 35 imol), lithium 5 chloride (293 mg, 6.9 mmol), then copper(I) iodide (13 mg, 69 pmol), and the mixture was heated at 80 0 C for 5 h. The reaction was cooled to ambient temperature then poured into water (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. 10 Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-1%), then by preparative thin-layer chromatography on silica gel using 5% methanol in dichloromethane as eluent, gave 1-(3'-bromobiphenyl-2-yl)-1H-[1,2,4]triazole as a colourless gel: in/z (ES+) 300, 302 (M++H). 15 1-(3'-Bromobiphenyl-2-yl)-1H-[1,2,4]triazole (91 mg, 0.30 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.25 mmol) by the method of Example 32. The product was obtained by preparative thin-layer chromatography on silica gel with 3% methanol in dichloromethane as eluent followed by high performance liquid 20 chromatography to give 3-[2'-([1,2,4]triazol-1-yl)biphenyl-3-yl)-7 trifluoromethylimidazo[1,2-a]pyrimidine as a yellow solid: SH (400 MHz, CDCls) 8.57 (1H, d, J 7), 7.95-8.11 (3H, m), 7.48-7.66 (7H, in), 7.35 (1H, d, J8), 7.27 (1H, m); mlz (ES+) 407 (M++H). 25 EXAMPLE 35 3'-[7-(Morpholin-4-vlmethyl)imidazo[1,2-alpyrimidin-3-vllbiphenvl-2 carbonitrile To a solution of 3'-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3 30 yl)biphenyl-2-carbonitrile (0.1 g, 0.31 mmol) in anhydrous dichloromethane under nitrogen was added carbon tetrabromide (153 mg, WO 01/90108 PCT/GBO1/02158 - 64 0.46 mmol) and triphenylphosphine (121 mg, 0.46 mmol). The resultant mixture was stirred for 6 h after which time morpholine (67 pd, 0.77 mmol) was added and the reaction stirred for a further 18 h. The solvent was evaporated in vacuo and the residue purified by silica gel chromatography 5 eluting with dichloromethane on a gradient of methanol (0-10%). Further purification by high performance liquid chromatography gave 3'-[7 (morpholin-4-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 carbonitrile trifluoroacetate salt (18.0 mg): 6 H (400 MHz, d6DMSO) 3.52 (4H, bs), 4.02 (4H, m), 4.64 (2H, s), 7.50-7.84 (9H, in), 8.12 (1H, bs), 9.17 10 (1H, s); n/z (ES+) 396 (M++H). EXAMPLE 36 4-Fluoro-3'-(7-trifluoromethylimidazor,2-alpyrimidin-3-vl)biphenvl-2 15 carbonitrile 2-Bromo-5-fluorobenzonitrile and 3-nitrophenylboronic acid were coupled following the procedure in Example 1 to afford 4-fluoro-3'-nitro biphenyl-2-carbonitrile as a black solid: 8H (360 MHz, CDCls) 7.39-7.48 (2H, in), 7.52-7.64 (1H, in), 7.71 (1H, dd, J 8 and 8), 7.89 (1H, d, J 8), 8.33 20 8.37 (2H, m). 4-Fluoro-3'-nitrobiphenyl-2-carbonitrile was reduced by treatment with tin(II) chloride in ethanol and tetrahydrofuran to give 3'-amino-4 fluorobiphenyl-2-carbonitrile as a brown solid: 6 H (360 MHz, CDCl 3 ) 6.76 (1H, ddd, J 8, 2 and 2), 6.80 (1H, dd, J 2 and 2), 6.87 (1H, ddd, J 8, 1 and 25 1), 7.27 (1H, dd, J8 and 8), 7.35 (1H, ddd, J8, 8 and 3), 7.41-7.51 (2H, m). 3'-Amino-4-fluorobiphenyl-2-carbonitrile was bromo-deaminated by treatment with 48% hydrobromic acid in 1,4-dioxane, then with sodium nitrite in water at <50C, then with copper(I) bromide in 48% hydrobromic acid, to give 3'-bromo-4-fluorobiphenyl-2-carbonitrile as a white solid: 8H 30 (400 MHz, CDCl 3 ) 7.35-7.40 (2H, m), 7.46-7.50 (3H, m), 7.59 (1H, dd, J 2 and 1), 7.64 (1H, dd, J 2 and 2).
WO 01/90108 PCT/GBO1/02158 - 65 3'-Bromo-4-fluorobiphenyl-2-carbonitrile was converted to 4-fluoro 3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile following the procedure in Example 1 to furnish a brown oil that crystallised on standing: 8H (400 MHz, CDCls) 1.36 (12H, s), 7.32-7.37 (1H, 5 m), 7.43-7.54 (3H, m), 7.63-7.68 (1H, in), 7.88-7.90 (2H, m). 3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine was coupled with 4-fluoro-3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2 carbonitrile as described in Example 1 to give 4-fluoro-3'-(7 trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (220 10 mg, 57%) as a yellow powder: 8H (400 MHz, CDCl 3 ) 7.29 (1H, d, J 7), 7.45 (1H, ddd, J8, 1 and 1), 7.53 (1H, dd, J8 and 3), 7.55-7.61 (2H, in), 7.65 7.67 (iH, m), 7.70-7.75 (1H, in), 7.77 (1H, s), 8.14 (1H, s), 9.14 (1H, d, J7); m/z (ES+) 383 (M++H). 15 EXAMPLE 37 4-Fluoro-3'-[7-(2-hydroxyprop-2-vl)imidazo[1,2-alpyrimidin-3-vllbiphenyl 2-carbonitrile 2-(3-Bromoimidazo[1,2-a]pyrimidin-7-yl)propan-2-ol was coupled 20 with 4-fluoro-3'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2 carbonitrile as described in Example 1 to give 4-fluoro-3'-[7-(2 hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (260 mg, 70%) as a yellow powder: 8H (360 MHz, CDCl 3 ) 1.61 (6H, s), 4.51 (1H, s), 7.07 (1H, d, J7), 7.45 (1H, ddd, J8, 1 and 1), 7.51-7.60 (3H, in), 25 7.63-7.69 (2H, m), 7.73 (1H, s), 7.90 (1H, s), 8.94 (1H, d, J 7); m/z (ES+) 373 (M++H). EXAMPLE 38 30 3-[3-(Pyridin-3-Vl)phenyll-7-trifluoromethvlimidazo[1,2-alpyrimidine WO 01/90108 PCT/GBO1/02158 - 66 A mixture of 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3 boronic acid-1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in EtOH (60 ml) and toluene (60 ml) together with 2N Na2COs solution (24.5 ml) was degassed with a stream of N 2 for 10 min. Tetrakis(triphenylphosphine) 5 palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 14 h. The mixture was concentrated under reduced pressure to remove the organic solvents. The organics were extracted with EtOAc (2 x 125 ml) and then washed with brine (75 ml), dried (MgSO 4 ), and concentrated under reduced pressure. The resulting crude residue was 10 purified by column chromatography on silica, using 80% diethyl ether in hexane as the eluent, to yield 3-(3-bromophenyl)pyridine (3.66 g, 64%): 6H (360 MHz, CDC13) 7.30-7.42 (2H, in), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J8 and 2), 8.62 (1H, dd, J 4.8 and 1.5), 8.83 (1H, s). A mixture of 3-(3-bromophenyl)pyridine (1.65 g, 7.1 mmol), bis 15 (neopentyl glycolato)diborane (1.75 g, 7.8 mmol), KOAc (2.1 g, 21.2 mmol) and Pd(dppf)C1 2 (288 mg, 5 mol %) in 1,4-dioxane (60 ml) was degassed with a stream of N 2 for 10 min and then heated at 110 0 C for 16 h. The reaction mixture was concentrated under reduced pressure and diethyl ether (150 ml) was added. This was extracted with 4N NaOH (3 x 50 ml). 20 These combined basic extracts were neutralised with conc. HCl and then extracted with dichloromethane (3 x 100 ml). The combined organic filtrates were washed with brine (50 ml) and dried (MgSO4) to yield 3-[3 (5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]pyridine (1.63 mg, 87%): 8H (360 MHz, CDC1 3 ) 5 1.04 (6H, s), 3.80 (4H, s), 7.38 (1H, dd, J 7.8 and 4.9), 25 7.47 (1H, t, J 7.8), 7.60-7.68 (1H, in), 7.84 (1H, d, J 7.4), 7.96 (1H, dt, J 7.8 and 2.0), 8.03 (1H, s), 8.58 (1H, dd, J 4.9 and 1.5), 8.85 (1H, s); m/z (ES+) 267 (M+H+). A mixture of 3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (300 mg, 1.12 mmol), the foregoing boronate ester (602 mg, 2.24 mmol), 2N 30 Na 2 COs solution (2.24 ml) and THF (4.5 ml) were degassed with a stream of N 2 for 5 min and then tetrakis(triphenylphosphine)palladium(0) (130 WO 01/90108 PCT/GBO1/02158 - 67 mg, 10 mol %) was added and the reaction was heated at 70*C for 90 min. EtOAc (70 ml) was added and the mixture separated, washed with brine (20 ml), dried (MgSO4) and concentrated under reduced pressure while dry loading onto MgSO 4 . The residue was purified by column chromatography 5 on silica using 70% EtOAc in hexanes containing 1% EtaN and 1% MeOH as the eluent. The resulting material was taken up in MeOH and poured onto a strong cation exchange cartridge and eluted with methanol. The product was then eluted with 2.OM NH 3 in MeOH and evaporated while dry loading onto silica. Subsequent purification by column 10 chromatography on silica using 2.5% MeOH in dichloromethane containing 1% NH 3 (aq.) gave 3-[3-(pyridin-3-yl)phenyl]-7 trifluoromethylimidazo[1,2-a]pyrimidine (120 mg, 31%): 8H (360 MHz, d 6 DMSO) 7.48-7.58 (2H, m), 7.73 (1H, t, J 7.7), 7.81 (1H, d, J 7.7), 7.87 (1H, d, J 7.7), 8.12 (1H, s), 8.21 (1H, dt, J8.1 and 2.0), 8.37 (1H, s), 8.62 (1H, 15 dd, J 4.8 and 1.5), 9.03 (1H, d, J 2), 9.42 (1H, d, J 7.2); in/z (ES+) 341 (M+). EXAMPLE 39 3-[3-([1,2,41Triazol-4-vl)phenvll-7-trifluoromethylimidazo[1,2-alpyrimidine 20 A mixture of 1,2-bis[(dimethylamino)methylene]hydrazine dihydrochloride (6.25 g, 29.0 mmol) and 3-bromoaniline (5.0 g, 29.0 mmol) in toluene (100 ml) was heated at reflux for 14 h. The resulting mixture was cooled to room temperature and H 2 0 (100 ml) added. The layers were separated and the organics were washed with brine (75 ml), dried 25 (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica, using 2% MeOH in EtOAc as the eluent, to yield 4-(3-bromophenyl)-4H-[1,2,4]triazole (3.33 g, 51%): 8H (360 MHz, CDCls) 7.32-7.38 (1H, m), 7.43 (1H, t, J8), 7.59 (1H, s), 7.63 (2H, d, J8), 8.47 (2H, s); m/z (ES+) 223, 225 (1:1) (M+). 30 4-(3-Bromophenyl)-4H-[1,2,4]triazole (2.5 g, 11.1 mmol), bis(neopentyl glycolato)diborane (2.77 g, 12.2 mmol), KOAc (3.3 g, 33.5 WO 01/90108 PCT/GBO1/02158 - 68 mmol) and Pd(dppf)Cl 2 (456 mg, 5 mol %) in 1,4-dioxane (100 ml) were reacted as described in Example 38 to yield 4-[3-(5,5-dimethyl [1,3,2]dioxaborinan-2-yl)phenyl]-4H-[1,2,4]triazole (0.78 g, 27%): 8H (360 MHz, CDCls) 1.04 (6H, s), 3.80 (4H, s), 7.40-7.50 (1H, in), 7.53 (1H, J7.5), 5 7.80 (1H, s), 7.89 (1H, d, J 7.5), 8.57 (2H, s); n/z (ES+) 257 (M++H). A mixture of 3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (139 mg, 0.53 mmol), the foregoing boronate ester (269 mg, 1.05 mmol) and K 3
PO
4 (483 mg, 2.1 mmol) in DMA (3 ml) was degassed with a stream of N 2 for 5 min and then tetrakis(triphenylphosphine)palladium(0) (60 mg, 10 10 mol %) was added and the reaction heated at 65'C for 70 min. EtOAc (100 ml) was added and the mixture washed with H 2 0 (3 x 100 ml) and brine (100 ml), dried (MgSO4) and concentrated under reduced pressure while dry loading onto silica. The residue was purified by column chromatography on silica using 5% MeOH in dichloromethane to yield 3 15 [3-([1,2,4]triazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine (70 mg, 40%), which was then recrystallised from EtOAc/isohexanes: 6 H (400 MHz, d 6 -DMSO) 7.55 (1H, d, J 7.2), 7.70-7.90 (3H, in), 8.16 (1H, s), 8.39 (1H, s), 9.24 (2H, s), 9.48 (1H, d, J 7.2); in/z (ES+) 331 (M+H+).
Claims (12)
1. A compound of formula I, or a salt or prodrug thereof: R N Y-Z 5 (I) wherein Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; 10 R 1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO 2 Ra, -SO 2 NRaRb, -NRaRb, -NRaCORb, -NRaCO 2 Rb, -CORa, -CO 2 Ra, -CONRaRb or -CRa=NORb; and Ra and Rb independently represent hydrogen, hydrocarbon or a 15 heterocyclic group.
2. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof: WO 01/90108 PCT/GBO1/02158 - 70 R N N (IIA) wherein Z is as defined in claim 1; 5 R 1 1 represents hydrogen, C 1 . 6 alkyl, halo(C1.6)alkyl, dihalo(C1.6)alkyl, hydroxy(C1.6)alkyl, C 1 . 6 alkoxy(CI.-)alkyl, di(C1.6)alkoxy(C.)alkyl, C 3 . 7 cycloalkyl, C3.7 heterocycloalkyl(C1.6)alkyl, heteroaryl, C 1 . 6 alkyl heteroaryl, heteroaryl(C1..6)alkyl, halogen, cyano, trifluoromethyl, C 1 6 alkoxy, formyl, C 2 - 6 alkylcarbonyl, C 2 . 6 alkoxycarbonyl or -CR 4 =NOR 5 ; 10 R 4 represents hydrogen or C1. 6 alkyl; and R5 represents hydrogen, C1- 6 alkyl, hydroxy(C.)alkyl or di(C1.)alkylamino(C1.6)alkyl.
3. A compound as claimed in claim 2 represented by formula 15 IIB, and salts and prodrugs thereof: H 3 C N (IIB) wherein Z is as defined in claim 1. WO 01/90108 PCT/GBO1/02158 - 71
4. A compound as claimed in claim 2 represented by formula IIC, and salts and prodrugs thereof: R N N R 6 R' 5 (IIC) wherein X represents CH or N; R6 represents fluoro, cyano, trifluoromethyl, methoxy, 10 methyloxadiazolyl, triazolyl or -CR 2 =NOR3; R7 represents hydrogen or fluoro; R 2 represents hydrogen or methyl; R 3 represents hydrogen, hydroxyethyl or dimethylaminoethyl; and R1 is as defined in claim 2. 15
5. A compound as claimed in claim 2 represented by formula IID, and salts and prodrugs thereof: WO 01/90108 PCT/GBO1/02158 - 72 R11 N N Rn N N NN \ N (IID) wherein W represents CH or N; and 5 R 11 is as defined in claim 2.
6. A compound selected from: 3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; and salts and prodrugs thereof. 10
7. A compound selected from: 3'-(imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 15 carbonitrile; 3'-(7-acetylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-isopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-cyclopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 20 3'-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-fluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 3'-(7-formylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; WO 01/90108 PCT/GBO1/02158 - 73 3'-(7-hydroxyiminomethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 carbonitrile; 3-(2'-cyanobiphenyl-3-yl)imidazo[1,2-a]pyrimidine-7-carbonitrile; 3-(2'-methoxybiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine; 5 3-(2'-cyanobiphenyl-3-yl)imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester; 3'-(7-dimethoxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 carbonitrile; 3'-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 10 carbonitrile; 3'-(7-difluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 7-methyl-3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-a]pyrimidine; 7-methyl-3-[3'-(5-methyl-[1,2,4]oxadiazol-3-yl)biphenyl-3-yl]imidazo[1,2 a]pyrimidine; 15 7-methyl-3-[2'-(3-methyl-[1,2,4]oxadiazol-5-yl)biphenyl-3-yl]imidazo[1,2 alpyrimidine; 7-methyl-3-[3-(thiazol-4-yl)phenyl]imidazo[1,2-a]pyrimidine; 3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbaldehyde oxime; 3-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile; 20 7-methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine; 7-methyl-3-[3-(thiazol-2-yl)phenyl]imidazo[1,2-a]pyrimidine; 7-methyl-3-(2'-trifluoromethylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine; 3-(2'-fluorobiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine; 4-fluoro-3'-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 25 3-[3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine; 3-[3-([1,2,4]triazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine; 3-[2'-([1,2,4]triazol-1-yl)biphenyl-3-yl]-7-trifluoromethylimidazo[1,2 a]pyrimidine; 3'-[7-(morpholin-4-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 30 carbonitrile; and salts and prodrugs thereof. WO 01/90108 PCT/GBO1/02158 - 74
8. A compound selected from: 4-fluoro-3'-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2 carbonitrile; 5 4-fluoro-3'-[7-(2-hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2 carbonitrile; 3-[3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine; 3-[3-([1,2,4]triazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine; and salts and prodrugs thereof. 10
9. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof in association with a pharmaceutically acceptable carrier. 15
10. The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of adverse neurological conditions. 20
11. A process for the preparation of a compound as claimed in claim 1, which comprises: (A) reacting a compound of formula III with a compound of formula IV: 25 1 Mi R(IV) (III) (IV) WO 01/90108 PCT/GBO1/02158 - 75 wherein Y, Z and R 1 are as defined in claim 1, L 1 represents a suitable leaving group, and M 1 represents a boronic acid moiety -B(OH) 2 or a cyclic ester thereof formed with an organic diol, or M 1 represents -Sn(Alk)3 in which Alk represents a C 1 . 6 alkyl group; in the presence of a transition 5 metal catalyst; or (B) reacting a compound of formula V with a compound of formula VI: R' ~N M "Y- Z (V) (VI) 10 wherein Y, Z and R1 are as defined in claim 1, and L 1 and M1 are as defined above; in the presence of a transition metal catalyst; or (C) reacting a compound of formula VII with a compound of formula VIII: R NN N 11 L 15 (VII) (VIII) wherein Z and R 1 are as defined in claim 1, and L 1 and M 1 are as defined above; in the presence of a transition metal catalyst; or (D) reacting a compound of formula IX with a compound of formula 20 X: WO 01/90108 PCT/GBO1/02158 - 76 R N N L-- Z M (IX) (X) wherein Z and R1 are as defined in claim 1, and L 1 and M 1 are as defined above; in the presence of a transition metal catalyst; or 5 (E) reacting a compound of formula X as defined above with a compound of formula XI: R N N OH (XI) 10 wherein R 1 is as defined in claim 1; or (F) reacting a compound of formula X as defined above with a compound of formula XII: RN N ~N NH 2 (XII) WO 01/90108 PCT/GBO1/02158 - 77 wherein R 1 is as defined in claim 1; or (G) reacting a compound of formula XVI with a compound of formula XVII: 5 L 3 CHO R N NH 2 Y-Z (XVI) (XVII) wherein Y, Z and R 1 are as defined in claim 1, and La represents a suitable leaving group; or 10 (H) reacting a compound of formula XXI with a compound of formula XXII: L 4 N N Ria _M Y-Z (XXII) 15 wherein Y and Z are as defined in claim 1, Ria represents an aryl or heteroaryl moiety, and L 4 represents a suitable leaving group; in the presence of a transition metal catalyst; and (J) if desired, converting a compound of formula I initially obtained into a further compound of formula I by standard methods. 20 WO 01/90108 PCT/GBO1/02158 - 78
12. A method for the treatment and/or prevention of adverse neurological conditions which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a 5 prodrug thereof.
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CN1871008A (en) * | 2003-10-21 | 2006-11-29 | 默克公司 | Triazolo-pyridazine compounds and derivatives thereof useful in the treatment of neuropathic pain |
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DK40192D0 (en) * | 1992-03-26 | 1992-03-26 | Neurosearch As | IMIDAZOLE COMPOUNDS, THEIR PREPARATION AND USE |
AU675484B2 (en) | 1993-03-24 | 1997-02-06 | Neurosearch A/S | Benzimidazole compounds, their use and preparation |
ES2150671T3 (en) | 1995-04-21 | 2000-12-01 | Neurosearch As | COMPOSITE OF BENCIMIDAZOL AND ITS USE AS MODULATORS OF THE GABA-A RECEIVER COMPLEX. |
AU742172B2 (en) | 1997-10-10 | 2001-12-20 | Neurosearch A/S | Benzimidazole compounds, pharmaceutical compositions containing the comp ounds and their use |
WO1999036423A1 (en) | 1998-01-14 | 1999-07-22 | Merck Sharp & Dohme Limited | Triazolo-pyridazine derivatives as ligands for gaba receptors |
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- 2001-05-17 AU AU56517/01A patent/AU783521B2/en not_active Ceased
- 2001-05-17 EP EP01929837A patent/EP1294723A1/en not_active Withdrawn
- 2001-05-17 CA CA002410037A patent/CA2410037C/en not_active Expired - Fee Related
- 2001-05-17 US US10/296,116 patent/US6642229B2/en not_active Expired - Fee Related
- 2001-05-17 JP JP2001586295A patent/JP2004501109A/en not_active Withdrawn
Cited By (1)
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AU2002343110B2 (en) * | 2001-11-28 | 2008-10-30 | Merck Sharp & Dohme Limited | Imidazopyridines, pyrimidines and triazines for enhancing cognition as GABA-A alpha 5 receptor subtype ligands |
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CA2410037A1 (en) | 2001-11-29 |
US6642229B2 (en) | 2003-11-04 |
JP2004501109A (en) | 2004-01-15 |
AU783521B2 (en) | 2005-11-03 |
US20030176449A1 (en) | 2003-09-18 |
EP1294723A1 (en) | 2003-03-26 |
WO2001090108A1 (en) | 2001-11-29 |
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